Aniline derivatives possessing an inhibitory effect of nitric oxide synthase

ABSTRACT

Compounds represented by the general formula (1): 
     
       
         
         
             
             
         
       
     
       
     (where R 1  is SR 6  or NR 7 R 8 , where R 6  is typically an alkyl group having 1-6 carbon atoms, R 7  is a hydrogen atom, an alkyl group having 1-6 carbon atoms or a nitro group, and R 8  is a hydrogen atom or an alkyl group having 1-6 carbon atoms; R 2  and R 3  are each typically a hydrogen atom or an alkyl group having 1-6 carbon atoms; R 4  is a hydrogen atom, an alkyl group having 1-6 carbon atoms or an amidino group of which the amine portion may be substituted by an alkyl or nitro group; R 5  is a hydrogen atom or an alkyl group having 1-6 carbon atoms; Y 1 , Y 2 , Y 3  and Y 4  which may be the same or different are each typically a hydrogen atom, a halogen atom or an alkoxy group having 1-6 carbon atoms; n and m are each an integer of 0 or 1), or possible stereoisomers or optically active forms of the compounds or pharmaceutically acceptable salts thereof. The compounds possess a potent nitric oxide synthase inhibiting activity and are useful as therapeutics of cerebrovascular diseases.

This application is a 371 of PCT/JP95/02540 filed Dec. 12, 1995 which is a continuation of PCT/JP95/01135 filed Jun. 7, 1995.

TECHNICAL FIELD

This invention relates to N-substituted aniline derivatives, more specifically to the compounds represented by the general formula (1) which have an inhibitory effect on nitric oxide synthase (NOS) to suppress the production of nitric oxide (NO) and thereby prove effective against the pathology in cerebrovascular diseases, in particular, occlusive cerebrovascular diseases in which excessive NO or NO metabolites would be involved, as well as traumatic brain injuries, seizure, headache and other pains, morphine tolerance and dependence, Alzheimer's disease, Parkinson's disease, septic shocks, chronic rheumatoid arthritis, osteoarthritis, viral or nonviral infections and diabetes; the invention also relates to possible stereoisomers and optically active forms of the compounds, pharmaceutically acceptable salts thereof, as well as to preventives and therapeutics containing them as an effective ingredient.

BACKGROUND ART

Occlusion or lower perfusion pressure in a cerebral artery or carotid artery by a certain mechanism cause ischemic necrosis in the brain tissue and this state is called “cerebral infarction”. Cerebral infarction is roughly classified to cerebral embolism and cerebral thrombosis depending upon the mechanism involved.

Cerebral embolism is characterized by the formation of thrombi in a cerebral artery due to detachment of intracardiac blood clots or rarely blood clots on arterial walls, and cerebral thrombosis is primarily based on sclerotic lesions of cerebral arteries, which are complicated by an increased blood viscosity or a reduced perfusion pressure to result in an occlusion of the artery, which may progress to ischemic necrosis of the brain tissue (“NOKEKKAN SHOGAI”, compiled under the supervision of Hisao MANABE and Teruo OMAE, published by Life Science, pp. 54-55, 1992).

Irrespective of whether the cause is cerebral embolism or thrombosis, the formation of edema is observed in the ischemic brain tissue either concurrently with or prior to the development of the infarction. Vasogenic brain edema is manifested several hours after the onset of cerebral ischemia and continues for about one week from the onset. Thereafter, the brain edema decreases gradually and, depending on the area of the infarction, the edema persists as an infarct area in one to three months. Since the brain is covered with the rigid skull, brain edema causes an increase in the brain volume. If the brain edema exceeds a certain limit, there occurs an abrupt increase in the tissue pressure and the intracranial pressure, often inducing fatal hernia and eventually aggravating the brain damage to determine the scope of the subsequent infarct volume (“CT, MRI JIDAI NO NOSOTCHUGAKU, PART I in Two Volumes”, Kenji INAMURA and Akio TERASHI, published by Nihon Rinshosha, pp.,231-239, 1993). In addition, if a region of the brain becomes infarcted, the functions that have been fulfilled by the affected area, for example, perception, sensation and memory will be lost.

Thus, the treatment of brain edema and infarction which are critical to the quality of patient's life and the prognosis of his disease is clinically a very important objective. As for brain edema, the currently used methods of treatment rely upon hyperpnea, the drainage of cerebrospinal fluid and the use of hypertonic solutions, steroids and others; however, in almost all the effects of cases, these methods are only transient and there is not much promise for the therapeutic efficacy to be finally achieved (“NOSOTCHU CHIRYO MANUAL”, ed. by Masakuni KAMEYAMA, published by Igaku Shoin, pp. 34-36, 1991). Therefore, it has been desirable to develop drugs that are operated by an entirely different mechanism than the conventional etiological observation and which will prove effective in the treatment of ischemic cerebrovascular diseases.

A presently dominant theory based on genetic DNA analyses holds that NOS exists in at least three isoforms, namely, calcium-dependent N-cNOS (type 1) which is present constitutively in neurons, calcium-dependent E-cNOS (type 3) which is present constitutively in vascular endothelial cells and apparently calcium-independent iNOS (type 2) which is induced and synthesized by stimulation with cytokines and/or lipopolysaccharides (LPS) in macrophages and many other cells (Nathan et al., FASEB J. 16, 3051-3064, 1992; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

A mechanism that has been proposed as being most probable for explaining the brain tissue damage which accompany cerebral ischemia is a pathway comprising the sequence of elevation in the extracellular glutamic acid level, hyperactivation of glutamic acid receptors on the post-synapses, elevation in the intracellular calcium level and activation of calcium-dependent enzymes (Siesjö, J. Cereb. Blood Flow Metab. 1, 155-185, 1981; Siesjö, J. Neurosurg. 60, 883-908, 1984; Choi, Trends Neurosci. 11, 465-469, 1988; Siejö and Bengstsson, J. Cereb. Blood Flow Metab. 9, 127-140, 1989). As already mentioned, N-cNOS is calcium-dependent, so the inhibition of abnormal activation of this type of NOS isoform would contribute to the neuroprotective effects of NOS inhibitors (Dawson et al., Annals Neurol. 32, 297-311, 1992).

As a matter of fact, the mRNA level of N-cNOS and the number of N-cNOS containing neurons start to increase early after cerebral ischemia and their temporal alterations coincide with the development of infarction in rats (Zhang et al., Brain Res. 654, 85-95, 1994). In addition, in a mouse model of focal cerebral ischemia, the percent inhibition of N-cNOS activity and the percent reduction of infarct volume correlate to each other at least in a dose range of L-NNA that reduces infarct volume (Carreau et al., Eur. J. Pharmacol. 256, 241-249, 1994). Further in addition, it has been reported that in N-cNOS knockout mice, the infarct volume observed after focal cerebral ischemia is significantly smaller than that in the control (Huang et al., Science 265, 1883-1885, 1994).

A report has also been made that suggests the involvement of iNOS in the mechanism for the occurrence and development of ischemic brain damage. Briefly, after 12 hours of focal cerebral ischemia in rats, the mRNA of iNOS started to increase in the cerebral cortex of the affected hemisphere and, after 2 days, it reached a maximum concomitantly with iNOS activity, probably originating from polynuclear leukocytes (Iadecola et al., J. Cereb. Blood Flow Metab. 15, 52-59, 1995; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 378-384, 1995). It has been reported that when N^(G)-nitro-L-arginine methyl ester (L-NAME) which is one of the NOS inhibitors was administered after 3 hours of ischemia in consideration of the above-described temporal changes, the infarct volume decreased significantly (Zhang et al., J. Cereb. Blood Flow Metab. 15, 595-601, 1995).

Further in addition, it has been reported that the amount of occurrence of iNOS or its enzymatic activity increased in astrocytes or brain microvessels after cerebral ischemia in rats (Endoh et al., Neurosci. Lett. 154, 125-128, 1993; Endoh et al., Brain Res. 651, 92-100, 1994; Nagafuji et al., in Brain Edema IX (Ito et al, eds.), 60, pp285-288, 1994, Springer-Verlag; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

These reports suggest that N-CNOS or iNOS may be closely involved in the mechanism for the occurrence and the development of the tissue damage following cerebral ischemia.

Referring now to NO, it is at least one of the essences of endothelium-derived relaxing factor (EDRF) and, hence, is believed to take part in the adjustment of the tension of blood vessels and the blood flow (Moncada et al., Pharmacol. Rev. 43, 109-142, 1991). As a matter of fact, it was reported that when rats were administered high doses of L-NNA, the cerebral blood flow was found to decrease in a dose-dependent manner as the blood pressure increased (Toru MATSUI et al., Jikken Igaku, 11, 55-60, 1993). The brain has a mechanism by which the cerebral blood flow is maintained at a constant level notwithstanding the variations of blood pressure over a specified range (which is commonly referred to as “autoregulation mechanism”) (“NOSOTCHU JIKKEN HANDBOOK”, compiled by Keiji SANO, published by IPC, 247-249, 1990). The report of Matsui et al. suggests the failure of this “autoregulation mechanism” to operate. Therefore, if E-cNOS is particularly inhibited beyond a certain limit in an episode of brain ischemia, the cerebral blood flow will decrease and the blood pressure will increase, thereby aggravating the dynamics of microcirculation, possibly leading to an expansion of the ischemic lesion.

The present inventors previously found that N^(G)-nitro-L-arginine (L-NNA), known to be a NOS inhibitor, possessd ameliorative effects against brain edema and infarction in a rat model of focal cerebral ischemia (Nagafuji et al., Neurosci. Lett. 147, 159-162, 1992; Japanese Patent Public Disclosure No. 192080/1994), as well as the neuronal cell death in a gerbil model of forebrain ischemia (Nagafuji et al., Eur. J. Pharmacol. Env. Tox. 248, 325-328, 1993). On the other hand, relatively high doses of NOS inhibitors have been reported to be entirely ineffective against ischemic brain damage or sometimes aggravating it (Iadecola et al., J. Cereb. Blood Flow Metab. 14, 175-192, 1994; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995). It should be noted that as a matter of fact, all papers that reported the changes of NO or its metabolites in the brain after permanent or temporary cerebral ischemia agreed in their results to show the increase in the levels of those substances (Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku, 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

One of the reasons for explaining the fact that conflicting reports have been made about the effectiveness of NOS inhibitors in cerebral ischemic models would be the low selectivity of the employed NOS inhibitors for N-cNOS or iNOS. As a matter of fact, no existing NOS inhibitors including L-NNA and L-NAME have a highly selective inhibitory effect on a specific NOS isoform (Nagafuji et al., Neuroreport 6, 1541-1545, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995). Therefore, it may well be concluded that desirable therapeutics of ischemic cerebrovascular diseases should have a selective inhibitory effect on N-cNOS or iNOS (Nowicki et al., Eur. J. Pharmacol. 204, 339-340, 1991; Dawson et al., Proc. Natl. Acad. Sci. USA 88, 6368-6371, 1991; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 52-59, 1995; Iadecola et al., J. Cereb. Blood Flow Metab. 15, 378-384, 1995; Toshiaki NAGAFUJI and Toru MATSUI, Jikken Igaku 13, 127-135, 1995; Nagafuji et al., Mol. Chem. Neuropathol. 26, 107-157, 1995).

It has also been suggested that N-cNOS inhibitors have the potential for use as therapeutics of traumatic brain injuries (Oury et al., J. Biol. Chem. 268, 15394-15398, 1993; MacKenzie et al., Neuroreport 6, 1789-1794, 1995), seizure (Rigaud-Monnet et al., J. Cereb. Blood Flow Metab. 14, 581-590; 1994), headache and other pains (Moore et al., Br. J. Pharmacol. 102, 198-202, 1991; Olesen., Trends Pharmacol. 15, 149-153, 1994), morphine tolerance and dependence (Kolesnikov et al., Eur. J. Pharmacol. 221, 399-400, 1992; Cappendijk et al., Neurosci. Lett. 162, 97-100, 1993), Alzheimer's disease (Hu and EI-FaKahany, Neuroreport 4, 760-762, 1993; Meda et al., Nature 374, 647-650, 1995) and Parkinson's disease (Youdim et al., Advances Neurol. 60, 259-266, 1993; Schulz et al., J. Neurochem. 64, 936-939, 1995).

Upon stimulation by certain kinds of cytokines and/or LPS, iNOS is induced in immunocytes such as macrophages and glial cells and other cells, and the resulting large amount of NO will dilate blood vessels to cause a fatal drop in blood pressure. Therefore, it is speculated that an iNOS inhibitor may be effective against septic shocks (Kilbourn and Griffith, J. Natl. Cncer Inst. 84, 827-831, 1992; Cobb et al., Crit. Care Med. 21, 1261-1263, 1993; Lorente et al., Crit. Care Med. 21, 1287-1295, 1993).

Further, it has been suggested that iNOS inhibitors are useful as therapeutics of chronic rheumatoid arthritis and osteoarthritis (Farrell et al., Ann, Rheum. Dis. 51, 1219-1222, 1992; Hauselmann et al., FEBS Lett. 352, 361-364, 1994; Islante et al., Br. J. Pharmacol. 110, 701-706, 1993), viral or nonviral infections (Zembvitz and Vane, Proc. Natl. Acad. Sci. USA 89, 2051-2055, 1992; Koprowski et al., Proc. Natl. Acad. Sci. USA 90, 3024-3027, 1993) and diabetes (Kolb et al., Life Sci. PL213-PL217, 1991).

The NOS inhibitors so far reported to have selectivity for N-cNOS are N^(G)-cyclpropyl-L-arginine (L-CPA) (Lamberte et al., Eur. J. Pharmacol. 216, 131-134, 1992), L-NNA (Furfine et al., Biochem. 32, 8512-8517, 1993), S-methyl-L-thiocitrulline (L-MIN) (Narayanan and Griffith, J. Med. Chem. 37, 885-887, 1994; Furfine et al., J. Biol. Chem. 37, 885-887, 1994; Furfine et al., J. Biol. Chem. 269, 26677-26683, 1994; W095/09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995; Nagafuji et al., Neuroreport 6, 1541-1545, 1995) and S-ethyl-L-thiocitrulline (L-EIN) (Furfine et al., J. Biol. Chem. 269, 26677-26683, 1994; W095/09619; Narayanan et al., J. Biol. Chem. 270, 11103-11110, 1995).

In addition, the inhibitors that have been reported to have selectivity for iNOS are N_(G)-iminoethyl-L-ornithine (L-NIO) (McCall et al., Br. J. Pharmacol. 102, 234-238, 1991) and aminoguanidine (AG) (Griffith et al., Br. J. Pharmacol. 110, 963-968, 1993; Hasan et al. Eur. J. Pharmacol. 249, 101-106, 1993)

DISCLOSURE OF INVENTION

An object of the present invention is to provide novel compounds that have a selective inhibitory effect on calcium-dependent NOS which is present constitutively in the brain, particularly in neurons (N-cNOS), or an apparently calcium-independent and inducible NOS (iNOS) and which are useful as therapeutics of cerebrovascular diseases, Alzheimer's disease, analgesics, morphine tolerance or dependence, sepsis, chronic rheumatoid arthritis, osteoarthritis, viral or nonviral infections, diabetes and Parkinson's disease.

As a result of the intensive studies made in order to attain the stated object, the present inventors found that N-substituted aniline derivatives represented by the general formula (1), or possible stereoisomers or optically active forms of the compounds, as well as pharmaceutically acceptable salts thereof have an inhibitory effect against or selectivity for N-cNOS or iNOS that are superior to the existing NOS inhibitors, thereby exhibiting marked effectiveness as therapeutics of cerebrovascular diseases (especially as therapeutics of occlusive cerebrovascular diseases):

 

(where

R₁ is SR₆ or NR₇R₈;

where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms;

R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 3-6 carbon atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkyl group having 1-6 carbon atoms, or a nitro group;

R₈ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms;

R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring;

R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring;

R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted acyl group having 1-8 carbon atoms, an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring;

R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycabonylamino group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amino group, or may combine with R₄ to form a 3- to 8-membered ring;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆, or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring;

Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and

n and m are each an integer of 0 or 1).

The present invention has been accomplished on the basis of this finding.

The present inventors also found that compounds represented by the general formula (21) are intermediates useful in the synthesis of the compounds represented by the general formula (1):

 

(where

R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₃ to form a 3- to 8-membered ring;

R₃ is a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₂ to form a 3- to 8-membered ring;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy groups having 1-6 carbon atoms of which the alkyl portion may optionally have a substituent, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring;

Y₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-6 carbon atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms, or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, or a cyclic alkyl group having 3-6 carbon atoms).

Japanese Patent Public Disclosure No. 13391/1975 ; Clin. Sci. Mol. Med. 53, 355-364, 1977; J. Chem. Eng. Data, 22, 3, 224-245, 1977; Clin. Sci. Mol. Med. 54, 673-677, 1978; J. Biochem. 94, 123-128, 1983 and International Publication WO94/21621 teach compounds that are related to the compounds of the invention which are represented by the general formula (1).

In addition, part of the compounds of the invention which are represented by the general formula (1) are described by generic concept in Japanese Patent Public Disclosure Nos. 97933/1977, 99227/1977 and 158249/1987. However, these patents make no reference whatsoever to the NOS inhibiting action of the compounds corresponding to those of the invention or other aspects thereof such as their use as therapeutics of cerebro-vascular diseases, traumatic brain injuries, seizure, Alzheimer's disease, Parkinson's disease, headache and other pains, morphine tolerance or dependence, septic shocks, chronic rheumatoid arthritis, osteoarthritis, viral or antiviral infections and diabetes.

It should also be noted that International Publication WO95/00505 which was not published before the priority date of the subject application (Dec. 12, 1994) but which was later published, and J. Chem. Soc. Perkin Trans. 1, 2025-2030, 1977 describe part of the compounds of the invention which are represented by the general formula (1), and said International Publication also shows part of the compounds of the invention by generic concept.

Further in addition, International Publication WO95/09619 which was not published before the priority date of the subject application (Dec. 12, 1994) but which was later published shows part of the compounds of the invention of the general formula (1) by generic concept.

As it will be demonstrated by the tests hereinafter, the compounds described in the Examples of the invention have by far superior NOS inhibiting action, as well as extremely high selectivity for both N-cNOS and iNOS compared to the compounds described in International Publication WO95/00505 and WO95/09619.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the efficacy of the compound of Example 96 in ameliorating the brain edema formed after 48-h occlusion of the left middle cerebral artery in rats; and

FIG. 2 is a graph showing the efficacy of the compound of Example 96 in ameliorating the brain infarction formed after 3-h occlusion of the left middle cerebral artery and subsequent 24-h reperfusion in rats.

BEST MODE FOR CARRYING OUT THE INVENTION

In the present invention,

the straight-chained or branched alkyl group having 1-6 carbon atoms may be exemplified by a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, pentyl or hexyl group or the like;

the straight-chained or branched alkenyl group having 2-6 carbon atoms may be exemplified by a vinyl, allyl, butenyl or pentenyl group or the like;

the cyclic alkyl group having 3-8 carbon atoms may be exemplified by a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group or the like;

the straight-chained or branched alkynyl group having 3-6 carbon atoms may be exemplified by a propynyl, butynyl or pentynyl group or the like;

the straight-chained or branched alkoxy group having 1-6 carbon atoms may be exemplified by a methoxy, ethoxy, i-propoxy or n-propoxy group or the like;

the alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms may be exemplified by a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl or t-butoxycarbonyl group or the like;

the acyl group having 1-8 carbon atoms may be exemplified by an acetyl, propionyl, butyryl, isobutyryl or benzoyl group or the like;

the straight-chained or branched alkylthio group having 1-6 carbon atoms may be exemplified by a methylthio, ethylthio or propylthio group or the like;

the substituent in the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or in the optionally substituted acyl group having 1-8 carbon atoms or in the optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms may be exemplified by a halogen atom, a hydrocarbyl group such as a phenyl group or the like;

the optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms may be exemplified by a methyl, ethyl, 2-fluoroethyl or n-propyl group or the like;

the optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms may be exemplified by a methoxy, ethoxy, trifluoromethoxy, propoxy or benzyloxy group or the like;

the optionally substituted acyl group having 1-8 carbon atoms may be exemplified by an acetyl or benzoyl group or the like;

NY₅Y₆ may be exemplified by an amino, methylamino, ethylamino, dimethylamino, ethylmethylamino, piperidino, acetamido, N-methylacetamido, t-butoxycarbonylamino or N-methyl-t-butoxycarbonylamino group or the like;

COY₇ may be exemplified by a formyl, carboxyl, acetyl, propionyl, cyclobutyryl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl or ethylmethylaminocarbonyl group or the like;

R₁ is preferably a mercapto group substituted by a straight-chained or branched alkyl group having 1-6 carbon atoms or an amino group substituted by a straight-chained or branched alkyl group having 1-6 carbon atoms or a nitroamino group, with a methylthio, ethylthio, ethylamino or nitroamino group being particularly preferred;

R₂ is preferably a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, with a hydrogen atom, a methyl group or an ethyl group being particularly preferred;

R₃ is preferably a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, with a hydrogen atom or a methyl group being particularly preferred;

the substituent in the case where R₂ and R₃ combine together to form a 3- to 8-membered ring may be exemplified by a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group;

R₄ is preferably a hydrogen atom;

R₅ is preferably a hydrogen atom;

m and n are preferably both 0 if the substituents other than Y₁, Y₂, Y₃ and Y₄ in the general formula (1) are m-substituted on the benzene nucleus and if the substituents other than Y₁, Y₂, Y₃ and Y₄ in the general formula (1) are p-substituted on the benzene nucleus, it is preferred that m is 1 and n is 0 or that m is 0 and n is 1;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each preferably a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may optionally be substituted by 1-3 halogen atom, a straight-chained or branched alkenyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, a methylamino group, an ethylamino group, a dimethylamino group or an ethylmethylamino group, and more preferred are a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms that may optionally be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may optionally be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, a methylamino group, an ethylamino group, a dimethylamino group and an ethylmethylamino group.

The compounds of the invention which are represented by the general formula (1) may typically be synthesized by the following schemes:

 

Among the compounds of the formula (1), one which is represented by the formula (6) with R₁ being SR₆ can be synthesized from a compound of the formula (3) via a compound of the formula (4).

The compound of the formula (6) (where

R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₃ to form a 3- to 8-membered ring;

R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₂ to form a 3- to 8-membered ring;

R₄ is an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms or an optionally substituted acyl group having 1-8 carbon atoms;

R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an alkoxycarbonylamino group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms;

R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms which may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms which may have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring;

Y₇ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-6 carbon atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms;

m is an integer of 0 or 1; and

n is an integer of 0 or 1) may be synthesized in the following manner, provided that R₂, R₃, R₄, R₅, R₆, Y₁, Y₂, Y₃, Y₄, m and n in the following formulae (3), (4), (5) and (6) are each the same as defined above and X is a bromine or iodine atom.

The compound represented by the formula (3) is reacted with thiophosgene in the presence of either an inorganic base such as calcium carbonate or potassium carbonate or an organic base such as triehtylamine or N,N-dimethylaminopyridine, preferably in the presence of calcium carbonate or N,N-dimethylaminopyridine, in a solvent inert to the reaction such as chloroform, methylene chloride, water or dimethylformamide, preferably in methylene chloride or a mixture of methylene chloride and water, at a temperature between 0° C. and the boiling point of the reaction mixture, preferably at room temperature, and the reaction product is thereafter treated with concentrated ammonia solution to yield the compound represented by the formula (4).

Then, the compound of the formula (4) is reacted with a compound of the formula (5) in a solvent inert to the reaction such as acetonitrile, acetone, 1,4-dioxane, methanol or ethanol at a temperature between room temperature and the boiling point of the reaction mixture, preferably in acetonitrile with the reaction mixture being heated under reflux, to thereby yield a compound of the formula (6).

Alternatively, the compound of the formula (6) (where

R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₃ to form a 3- to 8-membered ring;

R₄ and R₅ which may be the same or different are each a straight-chained or branched alkyl group having 1-6 carbon atoms or R₄ and R₅ may combine together to form a 3- to 8-membered ring;

R₃, Y₁, Y₂, Y₃, Y₄, X, m and n are each the same as defined above) may be synthesized in the following manner, provided that R₂, R₃, R₄, R₅, R₆, Y₁, Y₂, Y₃, Y₄, X, m and n in the following formulae (3), (4), (5) and (6) are each the same as defined above.

A compound represented by the formula (3) is reacted with benzoyl chloride and ammonium thiocyanate in a solvent inert to the reaction such as acetone at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature and, thereafter, the reaction mixture is heated under reflux together with an aqueous 10% sodium hydroxide solution to thereby yield a compound of the formula (4).

Subsequently, the compound of the formula (4) is reacted with an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid to form a quaternary ammonium salt, which in turn is reacted with a compound of the formula (5) in a solvent inert to the reaction such as acetonitrile, acetone, 1,4-dioxane, methanol or ethanol, at a temperature between room temperature and the boiling point of the reaction mixture, preferably in acetonitrile with the reaction mixture being heated under reflux to yield the compound of the formula (6).

Among the compounds of the formula (1), one which is represented by the formula (8) with R₁ being NR₇R₈, (where

R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms or may combine with R₃ to form a 3- to 8-membered ring;

R₄ is a straight-chained or branched alkyl group having 1-6 carbon atoms, a straight-chained or branched alkoxycarbonyl group having 1-6 carbon atoms, an optionally substituted acyl group having 1-8 carbon atoms or may combine with R₅ to form a 3- to 8-membered ring, provided that when R₅ is a hydrogen atom, R₄ is not an alkyl group;

R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms or an alkoxycarbonylamino group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms or may combine with R₄ to form a 3- to 8-membered ring;

R₇ is a straight-chained, branched or cyclic alkyl group having 1-6 carbon atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms or a straight-chained or branched alkynyl group having 3-8 carbon atoms;

R₈ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; and

R₃, Y₁, Y₂, Y₃, Y₄, m and n are each the same as defined above) may be synthesized with compounds of the formulae (6), (4) and (3) being used as starting materials, provided that R₂, R₃, R₄, R₅, R₇, R₈, Y₁, Y₂, Y₃, Y₄, X, m and n in the following formulae (3), (4), (5), (6), (7), (34), (35), (36) and (37) are each the same as defined above, with R₆ being an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms.

The compound of the formula (8) may be obtained by reacting a compound of the formula (6) with an amine of the formula (35) in a solvent inert to the reaction under heating, preferably in dimethylformamide at 80° C.

Alternatively, the compound of the formula (8) may be obtained by converting a compound of the formula (4) to a compound of the formula (34) in accordance with the method of C. A. Maryanoff et al. (J. Org. Chem. 51, 1882-1884, 1986) and thereafter reacting the compound (34) with the amine of the formula (35).

Further in addition, the compound of the formula (8) can be obtained by heating a compound of the formula (3) under reflux together with a compound of the formula (7) in a solvent such as pyridine.

Alternatively, the compound of the formula (8) may be obtained by reacting the compound of the formula (3) with a compound of the formula (36) in accordance with the method of M. A. Poss et al. (Tetrahedron Lett. 33, 5933-5936, 1992) so as to yield a compound of the formula (37) and by then removing the t-butoxycarbonyl protecting group under the conditions to be set forth below.

Among the compounds of the formula (1), one which is represented by the formula (9) with R₁ being NHNO₂ and one which is represented by the formula (10) with R₁ being NH₂ can be synthesized with the compound of the formula (3) being used as a starting material, provided that R₂, R₃, R₄, R₅, Y₁, Y₂, Y₃, Y₄, m and n in the following formulae (3), (9) and (10) are each the same as defined above.

The compound of the formula (9) may be obtained by reacting the compound of the formula (3) with N-methyl-N′-nitro-N-nitrosoguanidine or N-nitro-S-methylisothiourea in a solvent inert to the reaction such as acetonitrile, ethanol, methanol or water, preferably in acetonitrile, at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature, optionally in the presence of triethylamine or acetic acid.

The compound of the formula (10) may be obtained by a reduction of the compound represented by the formula (9). The reduction may be performed in a solvent inert to the reaction such as methanol in the presence of formic acid and palladium-black at room temperature.

Among the compounds of the formula (1), one in which R₄ is a hydrogen atom may be synthesized in the following manner.

Among the compounds represented by the formulae (6), (8), (9) or (10), those in which R₄ is an alkoxycarbonyl protective group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms are deprotected by treatment with a deprotecting agent to yield compounds in which R₄ is a hydrogen atom. The deprotection may be carried out under those conditions which are customarily used in accordance with the specific type of the protective group to be removed. For instance, if R₄ is a t-butoxycarbonyl group, the deprotection is preferably carried out in a solvent inert to the reaction such as methylene chloride, ethyl acetate, methanol, ethanol, 1,4-dioxane or water or in the absence of any solvents at a temperature between 0° C. and room temperature in the presence of a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid and it is particularly preferred to use trifluoroacetic acid at room temperature under anhydrous conditions. It should however be noted that those compounds in which R₂, Y₁, Y₂, Y₃ and Y₄ are each a t-butoxycarbonyl group are converted to such compounds that each of the substituents mentioned above is a carboxyl group whereas those compounds in which R₅ is a t-butoxycarbonylamino group are converted by the deprotection to such compounds that R₅ is an amino group.

 

Among the compounds of the formula (1), those which are represented by the formulae (12) and (13) can be synthesized with a compound of the formula (11) used as a starting material, provided that R₇, R₈, X and n in the following formulae (7), (12) and (13) are each the same as defined above.

The compound represented by the formula (12) can be obtained by heating the compound of the formula (11) which is a compound of the formula (9) in which R₂, R₃, R₄, R₅, Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom and m is 0 under reflux together with a compound of the formula (7) in a solvent such as pyridine.

In addition, the compound represented by the formula (13) can be obtained by reacting the compound of the formula (11) with N-methyl-N′-nitro-N-nitrosoguanidine in a solvent such as pyridine at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature.

The compound of the formula (3) from which the compounds of the formula (1) are to be produced may typically be prepared by the following schemes:

 

The compound of the formula (3) (where

R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or it may combine with R₃ to form a 3- to 8-membered ring;

R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms or it may combine with R₂ to form a 3- to 8-membered ring;

R₄ is a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an optionally substituted acyl group having 1-8 carbon atoms or it may combine with R₅ to form a 3- to 8-membered ring;

R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or an alkoxycarbonylamino group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or it may combine with R₄ to form a 3- to 8-membered ring;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group of which the alkyl portion may optionally have a substituent, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms, or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring;

Y₇ is a straight-chained or branched alkoxy group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms;

m is an integer of 0 or 1; and

n is an integer of 0 or 1) can be synthesized with a compound of the formula (2) used as a starting material, provided that R₂, R₃, R₄, R₅, Y₁, Y₂, Y₃, Y₄, m and n in the following formulae (2) and (3) are each the same as defined above.

The compound of the formula (2) is subjected to a catalytic reduction in a solvent inert to the reaction such as ethanol, methanol, ethyl acetate, acetic acid or 1,4-dioxane, preferably in ethanol or methanol, in a hydrogen atmosphere at a temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature, with palladium-carbon, Raney nickel or platinum oxide being used as a catalyst; alternatively, the compound of the formula (2) is subjected to a reduction with nickel (II) chloride and sodium borohydride, etc.; in either way, the nitro group in the compound of the formula (2) is reduced to yield the compound of the formula (3).

Those compounds of the formula (3) in which R₄ is an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms may also be obtained by converting the amino group represented by NHR₅ in those compounds of the formula (3) where R₄ denotes a hydrogen atom into carbamate. If R₄ is a methoxycarbonyl group, above reaction to form carbamate which has an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms can be performed with methyl chloro-carbonate in a solvent inert to the reaction such as methylene chloride, in the presence of an organic base such as triethylamine or N,N-dimethylaminopyridine at a temperature between 0° C. and room temperature. If R₄ is a t-butoxycarbonyl group, the reaction can be performed with di-t-butyl dicarbonate in a solvent inert to the reaction such as methylene chloride, dimethylformamide or a mixture of 1,4-dioxane and water in the presence of an organic base such as triethylamine or N,N-dimethylaminopyridine or an inorganic base such as sodium hydroxide or sodium bicarbonate at a temperature between 0° C. and room temperature.

Among the compounds of the formula (3), one which is represented by the formula (44) (where

R₉ is a straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkoxy group having 1-6 carbon atoms;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms that may optionally be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms which may have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring) can be synthesized with compounds of the formulae (38) and (39) used as starting materials, provided that R₉ in the following formulae (38), (39), (40), (41), (42), (43) and (44) is the same as defined above and R₁₁ is an amino group protected with a t-butoxycarbonyl group, a phthaloyl group, a trifluoroacetyl group or the like and further that Y₁, Y₂, Y₃ and Y₄ in the following formulae (38), (41), (42), (43) and (44) are each the same as defined above.

By replacing the primary hydroxyl group in the compound of the formula (38) with a bromine atom, one can obtain a compound of the formula (40) (where Y₁, Y₂, Y₃ and Y₄ are each the same as defined above). The bromination can be performed in a solvent inert to the reaction such as methylene chloride in the presence of carbon tetrabromide and triphenylphosphine at a temperature between 0° C. and room temperature.

In addition, the compound of the formula (40) (where

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkoxy group having 1-6 carbon atoms which may optionally have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom or an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring) can also be obtained by reacting a compound of the formula (39) (where Y₁, Y₂, Y₃ and Y₄ are each the same as defined above) with N-bromosuccinimide in a solvent inert to the reaction such as carbon tetrachloride or benzene in the presence of α,α′-azobis(isobutyronitrile) under reflux with heating.

Then, the compound of the formula (40) (where

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may optionally be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms which may optionally have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring) is reacted with sodium cyanide or potassium cyanide to yield a compound of the formula (41). The amino protecting group in the resulting compound of the formula (41) is deprotected to yield a compound of the formula (42), which is then reacted with a hydrogenating reducing agent, preferably lithium aluminum hydride, in the presence of sulfuric acid in a solvent inert to the reaction such as ether or tetrahydrofuran, preferably in ether at a temperature between room temperature and the boiling point of the reaction mixture, preferably under reflux with heat, whereby the cyano group is reduced to yield a compound of the formula (43). The aliphatic amino group in the compound of the formula (43) in turn is acylated or converted to a carbamate with a compound of the formula (28) or (29) to yield a compound of the formula (44). If R₉ is a methyl group, the acylation of the amino group can be performed by reacting the compound of the formula (43) with an acetylation agent such as acetyl chloride or acetic anhydride in a solvent inert to the reaction such as methylene chloride in the presence of an organic base such as triethylamine or N,N-dimethylaminopyridine at a temperature between 0° C. and room temperature.

The compounds of the formula (2) from which the compounds of the formula (3) are to be produced can typically be prepared by the following schemes.

 

Among the compounds of the formula (2), one which is represented by the formula (17) (where

R₄ and R₅ which may be the same or different are each a straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, R₄ and R₅ may combine together to form a 3- to 8-membered ring;

n is an integer of 1 or 2;

Y₁, Y₂, Y₃ and Y₄ are each the same as defined above) can be synthesized from a compound of the formula (27) via compounds of the formulae (14) and (15), provided that R₄, R₅, Y₁, Y₂, Y₃, Y₄ and n in the following formulae (27), (14), (15), (16) and (17) are each the same as defined above and X is a chlorine atom or a bromine atom.

The carboxyl group in the compound of the formula (27) is reduced with a reducing hydrogenating agent, preferably diborane, by heating under reflux in a solvent inert to the reaction, such as tetrahydrofuran, so as to yield the compound of the formula (14).

Then, the primary hydroxyl group in the compound of the formula (14) is replaced by a halogen atom under ordinary reaction conditions to yield the compound of the formula (15). If X is a chlorine atom, the halogenation reaction may be performed with thionyl chloride in a solvent inert to the reaction such as benzene in the presence of a suitable base such as pyridine at a temperature between 0° C. and room temperature.

The resulting compound of the formula (15) in turn is reacted with an amine of the formula (16) in a solvent inert to the reaction such as dimethylformamide in the presence of an organic base such as triethylamine or N,N-dimethylaminopyridine or an inorganic base such as sodium bicarbonate or potassium carbonate at a temperature between 0° C. and room temperature to yield the compound of the formula (17).

Among the compounds of the formula (2), one which is represented by the formula (17) (where

R₄ and R₅ are both an alkoxycarbonyl group of which the alkyl portion is straight-chained or branched with 1-6 carbon atoms;

n is 1; and

Y₁, Y₂, Y₃ and Y₄ are each the same as defined above) can be synthesized in the following manner, provided that R₄, R₅, X, Y₁, Y₂, Y₃, Y₄ and n in the following formulae (15), (16) and (17) are each the same as defined above.

The compound of the formula (15) is reacted with a compound of the formula (16) in a solvent inert to the reaction such as dimethylformamide in the presence of sodium hydride at a temperature between 0° C. and room temperature to yield the compound of the formula (17).

Among the compounds of the formula (2), one which is represented by the formula (30) (where

R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms which may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group which may have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms; or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring;

Y₇ is a straight-chained or branched alkoxy group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms;

R₉ and n are each the same as defined above) can be synthesized from compounds of the formulae (15) and (19) via a compound of the formula (18), provided that X, Y₁, Y₂, Y₃, Y₄ and n in the following formulae (15), (18), (19), (20), (28), (29) and (30) are each the same as defined above.

By reacting the compound of the formula (15) with ammonia in a solvent inert to the reaction such as hydrous dimethyl sulfoxide at a temperature between 0° C. and room temperature, one can obtain the compound of the formula (18) (where R₅ is a hydrogen atom).

In addition, by subjecting the compound of the formula (19) to a reductive amination with an amine of the formula (20) (where R₅ is a straight-chained or branched alkyl group having 1-6 carbon atoms), one can obtain the compound of the formula (18) (where R₅ is the same as defined above). The reductive amination can be performed with a suitable reducing agent such as sodium cyanoborohydride in a solvent inert to the reaction such as ethanol or methanol at a temperature between 0° C. and room temperature.

Then, the amino group in the compound of the formula (18) (where R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms) is acylated or converted to a carbamate in the same manner as described above to yield a compound of the formula (30) (where R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms).

Among the compounds of the formula (2), one which is represented by the formula (32) (where

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms which may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms which may have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms, or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring:

Y₇ is a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-6 carbon atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms;

R₉ and n are each the same as defined above) can be synthesized from the compounds of the formulae (14) and (15) via a compound of the formula (31), provided that R₉, X, Y₁, Y₂, Y₃, Y₄ and n in the following formulae (14), (15), (28), (29), (31) and (32) are each the same as defined above.

The compound of the formula (31) can be obtained either by subjecting the compound of the formula (14) and phthalimide to Mitsunobu reaction or by reacting the compound of the formula (15) with potassium phthalimide in a solvent inert to the reaction such as dimethylformamide at room temperature.

Then, the phthalimide protecting group in the compound of the formula (31) is deprotected in the presence of hydrazine and, thereafter, conversion to a carbamate or acylation is performed in the same manner as described above to thereby yield the compound of the formula (32).

Among the compounds of the formula (2), one which is represented by the formula (22) (where

R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms or, alternatively, R₂ and R₃ may combine together to form a 3- to 8-membered ring;

R₁₀ is a straight-chained or branched alkyl group having 1-6 carbon atoms;

Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms which may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms which may be substituted by 1-3 halogen atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms which may have a substituent in the alkyl portion, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, an acyl group having 1-8 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or, alternatively, Y₅ and Y₆ may combine together to form a 3- to 8-membered ring;

Y₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-6 carbon atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms or NY₅Y₆;

where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms) can be obtained by subjecting a compound of the formula (21) (where R₂, R₃, Y₁, Y₂, Y₃ and Y₄ are each the same as defined above) to a Curtius rearrangement reaction and to the addition reaction of various alcohols of the formula (33) (where R₁₀ is the same as defined above). The Curtius rearrangement reaction and the addition reaction of various alcohols can be performed by reacting the compound of the formula (21) (where R₂, R₃, Y₁, Y₂, Y₃ and Y₄ are each the same as defined above) with a reagent such as diphenylphosphorylazide at room temperature for producing an acid azide from a carboxylic acid and by then reacting the acid azide with an alcohol such as methanol, ethanol or t-butanol under reflux with heat. Alternatively, the reactions may be performed by reacting the compound of the formula (21) with a reagent such as diphenylphosphorylazide under reflux with heat for producing an acid azide from a carboxylic acid in an alcohol such as methanol, ethanol or t-butanol in the presence of an organic base such as triethylamine or N,N-dimethylaminopyridine.

Among the compounds of the formula (2), one which is represented by the formula (24) (where

R₉ is a straight-chained or branched alkoxy group having 1-6 carbon atoms; and

R₁₀ is the same as defined above) can be obtained by converting the amino group in a compound of the formula (23) to carbamate in the same manner as described above and thereafter performing an esterification in the usual manner. The esterification can typically be performed using a suitable condensing agent and various alcohols in a solvent inert to the reaction in the presence of an organic base at 0° C.-50° C. In the case of producing a t-butyl ester, the reaction may be performed with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and t-butanol in methylene chloride in the presence of an organic base such as triethylamine or N,N-dimethylaminopyridine at 0° C.-50° C., preferably at room temperature. Alternatively, in the case of producing a methyl ester, the reaction may be performed with trimethylsilyldiazomethane in a solvent inert to the reaction such as methanol or ether which are used either individually or in admixture at temperature between 0° C. and room temperature.

Among the compounds of the formula (2), one which is represented by the formula (26) (where R₉ and R₁₀ are each the same as defined above) can be obtained from a compound of the formula (25) by first converting it to 3- or 4-nitro-DL-phenylglycine in accordance with the method of H. Tsunematsu et al. (Journal of biochemistry 88, 1773-1783, 1980) and thereafter converting the amino group to a carbamate in the same manner as described above and then performing an esterification.

If the compounds of the invention which are represented by the general formula (1) have asymmetric carbons in their structure the pure forms of their stereoisomers and optically active forms thereof can be obtained by known techniques in the art, such as chromatography on optical isomer separating columns and fractional crystallization.

The compounds of the invention which are represented by the general formula (1) may be converted to any pharmaceutically acceptable salts which include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid and hydroiodic acid, salts with organic acids such as formic acid, acetic acid, oxalic acid and tartaric acid, salts with alkali metals such as sodium and potassium, and salts with alkaline earth metals such as calcium and magnesium.

The compounds of the invention or salts thereof may be formulated with suitable excipients, adjuvants, lubricants, antiseptics, disintegrators, buffering agents, binders, stabilizers, wetting agents, emulsifiers, coloring agents, flavoring agents, fragrances, etc. to form tablets, granules, subtilized granules, powders, capsules, syrups, elixirs, suspensions, emulsions, injections, etc. for oral or parenteral administration. When the cerebrovascular diseases to be treated are in a hyperacute phase (immediately after the stroke), an acute phase (from the stroke to 2 or 3 days later) or in a subacute phase (2 or 3 days up to 2 weeks after the stroke), the administration is anticipated to be primarily by intramuscular or intravenous injection. In addition, oral administration may be performed in a chronic phase (the third week after stroke and onward) if the patient admits ingestion.

The compounds of the invention or salts thereof may be administered in doses that vary with the physical constitution of the patient, his or her age, physical condition, the severity of the disease, the time of lapse after the onset of the disease and other factors; typical daily doses are anticipated to range from 0.1 to 100 mg/body. It should generally be noted that even if the same dose is administered, the plasma concentration may sometimes vary considerably between patients; hence, an optimal dose of the drug should ideally be determined for each patient on the basis of a monitored plasma concentration of the drug.

If the compounds of the invention or salts thereof are to be formulated as preparations for internal application, lactose, sucrose, sorbitol, mannitol, starches such as potato starch or corn starch, starch derivatives and common additives such as cellulose derivatives or gelatin are suitably used as vehicles, with lubricants such as magnesium stearate, carbowaxes and polyethylene glycol being optionally added concurrently; the resulting mixtures may be formulated in the usual manner into granules, tablets, capsules or other forms suitable for internal application.

If the compounds of the invention or salts thereof are to be formulated as aqueous preparations, effective amounts of the principal ingredients may be dissolved in distilled water for injection, with antioxidants, stabilizers, dissolution aids, buffering agents, preservatives, etc. added as required and, after complete solutions are formed, they are filtered, filled into ampules, sealed and sterilized by a suitable medium such as high-pressure vapor or dry heat so as to prepare injections.

If the compounds of the invention or salts thereof are to be formulated as lyophilized preparations, aqueous solutions having the principal ingredients dissolved in distilled water for injection may be freeze-dried in the usual manner, optionally after the addition of excipients that provide for easy lyophilization, such as sugars (e.g. lactose, maltose and sucrose), sugar alcohols (e.g. mannitol and inositol), glycine and the like.

The production of the compounds of the invention will now be described in greater detail with reference to the following examples but it should be understood that the invention is by no means limited to those examples.

In addition, in order to demonstrate the utility of the invention, the selective inhibitory effect of compounds of the general formula (1) on three NOS isoforms and their ameliorative effect against an occlusive cerebrovascular disease in a rat model of stroke were examined and the results are shown below under the Tests.

EXAMPLES

Tables 1-26 show the formulae for the chemical structures of the compounds prepared in the respective Examples.

TABLE 1

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

 

TABLE 2

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

Example 41

Example 42

Example 43

Example 44

Example 45

Example 46

Example 47

Example 48

Example 49

Example 50

Example 51

Example 52

Example 53

Example 54

 

TABLE 3

Example 55

Example 56

Example 57

Example 58

Example 59

Example 60

Example 61

Example 62

Example 63

Example 64

Example 65

Example 66

Example 67

Example 68

Example 69

Example 70

Example 71

Example 72

Example 73

Example 74

Example 75

Example 76

Example 77

Example 78

Example 79

Example 80

Example 81

 

TABLE 4

Example 82

Example 83

Example 84

Example 85

Example 86

Example 87

Example 88

Example 89

Example 90

Example 91

Example 92

Example 93

Example 94

Example 95

Example 96

Example 97

Example 98

Example 99

Example 100

Example 101

Example 102

Example 103

Example 104

 

TABLE 5

Example 105

Example 106

Example 107

Example 108

Example 109

Example 110

Example 111

Example 112

Example 113

Example 114

Example 115

Example 116

Example 117

Example 118

Example 119

Example 120

Example 121

Example 122

Example 123

Example 124

Example 125

Example 126

Example 127

Example 128

 

TABLE 6

Example 129

Example 130

Example 131

Example 132

Example 133

Example 134

Example 135

Example 136

Example 137

Example 138a

Example 138b

Example 139

Example 140

Example 141

Example 142

Example 143

Example 144

Example 145

Example 146

Example 147a

Example 147b

Example 148

Example 149

Example 150

 

TABLE 7

Example 151

Example 152

Example 153

Example 154

Example 155

Example 156a

Example 156b

Example 157

Example 158

Example 159

Example 160

Example 161

Example 162

Example 163a

Example 163b

Example 164

Example 165

Example 166

Example 167

Example 168

Example 169

Example 170

Example 171

Example 172

 

TABLE 8

Example 173

Example 174

Example 175

Example 176

Example 177

Example 178a

Example 178b

Example 179

Example 180

Example 181

Example 182

Example 183

Example 184

Example 185

Example 186

Example 187

Example 188

Example 189

Example 190

Example 191

Example 192

Example 193

Example 194

Example 195

 

TABLE 9

Example 196

Example 197

Example 198

Example 199

Example 200

Example 201

Example 202

Example 203

Example 204

Example 205

Example 206

Example 207

Example 208

Example 209

Example 210

Example 211

Example 212

Example 213

Example 214

Example 215

Example 216

Example 217

Example 218

 

TABLE 10

Example 219

Example 220

Example 221

Example 222

Example 223

Example 224

Example 225

Example 226

Example 227

Example 228

Example 229

Example 230

Example 231

Example 232

Example 1a

Example 1b

Example 1c

Example 8a

Example 8b

Example 15a

Example 15b

 

TABLE 11

Example 233

Example 234

Example 235

Example 236

Example 237

Example 238

Example 239

Example 240

Example 241

Example 242

Example 243

Example 244

Example 245

Example 246

Example 247

Example 248

Example 249

Example 250

Example 251

Example 252

Example 253

Example 254

Example 255

Example 256

Example 257

Example 258

Example 259

 

TABLE 12

Example 260

Example 262

Example 262

Example 263

Example 264

Example 265

Example 266

Example 267

Example 268

Example 269

Example 270

Example 271

Example 272

Example 273

Example 274

Example 275

Example 276

Example 277

Example 278

Example 279

Example 280

Example 281

Example 282

Example 283

Example 284

Example 285

Example 286

 

TABLE 13

Example 287

Example 288

Example 289

Example 290

Example 291

Example 292

Example 293

Example 294

Example 295

Example 296

Example 297

Example 298

Example 299

Example 300

Example 301

Example 302

Example 303

Example 304

Example 305

Example 306

Example 307

Example 308

Example 309

Example 310

Example 311

Example 312

Example 313

 

TABLE 14

Example 314

Example 315

Example 316

Example 317

Example 318

Example 319

Example 320

Example 321

Example 322

Example 323

Example 324

Example 325

Example 326

Example 327

Example 328

Example 329

Example 330

Example 331

Example 332

Example 333

Example 334

Example 335

Example 336

Example 337

Example 338

Example 339

Example 340

 

TABLE 15

Example 341

Example 342

Example 343

Example 344

Example 345

Example 346

Example 347

Example 348

Example 349

Example 350

Example 351

Example 352

Example 353

Example 354

Example 355

Example 356

Example 357

Example 358

Example 359

Example 360

Example 361

Example 362

Example 363

Example 364

Example 365

Example 366

Example 367

 

TABLE 16

Example 368

Example 369

Example 370

Example 371

Example 372

Example 373

Example 374

Example 375

Example 376

Example 377

Example 378

Example 379

Example 380

Example 381

Example 382

Example 383

Example 384

Example 385

Example 386

Example 387

Example 388

Example 389

Example 390

Example 391

Example 392

Example 393

Example 394

 

TABLE 17

Example 395

Example 396

Example 397

Example 398

Example 399

Example 400

Example 401

Example 402

Example 403

Example 404

Example 405

Example 406

Example 407

Example 408

Example 409

Example 410

Example 411

Example 412

Example 413

Example 414

Example 415

Example 416

Example 417

Example 418

Example 419

Example 420

Example 421

 

TABLE 18

Example 422

Example 423

Example 424

Example 425

Example 426

Example 427

Example 428

Example 429

Example 430

Example 431

Example 432

Example 433

Example 434

Example 435

Example 436

Example 437

Example 438

Example 439

Example 440

Example 441

Example 442

Example 443

Example 444

Example 445

Example 446

Example 447

Example 448

 

TABLE 19

Example 449

Example 450

Example 451

Example 452

Example 453

Example 454

Example 455

Example 456

Example 457

Example 458

Example 459

Example 460

Example 461

Example 462

Example 463

Example 464

Example 465

Example 466

Example 467

Example 468

Example 469

Example 470

Example 471

Example 472

Example 473

Example 474

Example 475

 

TABLE 20

Example 476

Example 477

Example 478

Example 479

Example 480

Example 481

Example 482

Example 483

Example 484

Example 485

Example 486

Example 487

Example 488

Example 489

Example 490

Example 491

Example 492

Example 493

Example 494

Example 495

Example 496

Example 497

Example 498

Example 499

Example 500

Example 501

Example 502

 

TABLE 21

Example 503

Example 504

Example 505

Example 506

Example 507

Example 508

Example 509

Example 510

Example 511

Example 512

Example 513

Example 514

Example 515

Example 516

Example 517

Example 518

Example 519

Example 520

Example 521

Example 522

Example 523

Example 524

Example 525

Example 526

Example 527

Example 528

Example 529

 

TABLE 22

Example 530

Example 531

Example 532

Example 533

Example 534

Example 535

Example 536

Example 537

Example 538

Example 539

Example 540

Example 541

Example 542

Example 543

Example 544

Example 545

Example 546

Example 547

Example 548

Example 549

Example 550

Example 551

Example 552

Example 553

Example 554

Example 555

Example 556

 

TABLE 23

Example 557

Example 558

Example 559

Example 560

Example 561

Example 562

Example 563

Example 564

Example 565

Example 566

Example 567

Example 568

Example 569

Example 570

Example 571

Example 572

Example 573

Example 574

Example 575

Example 576

Example 577

Example 578

Example 579

Example 580

Example 581

Example 582

Example 583

 

TABLE 24 Example 584

Example 585

Example 586

Example 587

Example 588

Example 589

Example 590

Example 591

Example 592

Example 593

Example 594

Example 595

Example 596

Example 597

Example 598

Example 599

Example 600

Example 601

Example 602

Example 603

Example 604

Example 605

Example 606

Example 607

Example 608

Example 609

Example 610

 

TABLE 25 Example 611

Example 612

Example 613

Example 614

Example 615

Example 616

Example 617

Example 618

Example 619

Example 620

Example 621

Example 622

Example 623

Example 624

Example 625

Example 626

Example 627

Example 628

Example 629

Example 630

Example 631

Example 632

Example 633

Example 634

Example 635

Example 636

Example 637

 

TABLE 26 Example 638

Example 639

Example 640

Example 641

Example 642

Example 643

Example 644

Example 645

Example 646

Example 647

Example 648

Example 649

Example 650

Example 651

Example 652

Example 653

Example 654

Example 655

Example 656

Example 657

Example 658

Example 659

Example 660

Example 661

Example 662

Example 663

Example 664

 

Among the compounds synthesized in the Examples, those which are represented by the general formula (1) are listed below in Tables 27-48.

TABLE 27

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 4 SMe 2-H 4-H 5-H 6-H 3 0 Me Me 0 ^(t)BuOCO H HI 5 SMe 2-H 4-H 5-H 6-H 3 0 Me Me 0 H H HCl 6 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Me Me 0 ^(t)BuOCO H — 7 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Me Me 0 H H HCl 11 SMe 2-H 4-H 5-H 6-H 3 0 Me H 0 ^(t)BuOCO H HI 12 SMe 2-H 4-H 5-H 6-H 3 0 Me H 0 H H HCl 13 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Me H 0 ^(t)BuOCO H — 14 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Me H 0 H H HCl 18 SMe 2-H 4-H 5-H 6-H 3 0 Et H 0 ^(t)BuOCO H HI 19 SMe 2-H 4-H 5-H 6-H 3 0 Et H 0 H H HCl 20 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Et H 0 ^(t)BuOCO H — 21 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Et H 0 H H HCl 25 SMe 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H HI 26 SMe 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 27 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H HI *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 28

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 28 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 29 SCH₂CH₂F 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H — 30 SCH₂CH₂F 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 31 SCH₂CH═CH₂ 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H HBr 32 SCH₂CH═CH₂ 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 33 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H — 34 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 H H — 35 NH₂ 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H HCOOH 36 NH₂ 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 39 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 Me Me CH₂COOH 41 SMe 2-H 4-H 5-H 6-H 3 0 H H 0 Me Me HNO₃, HCl 46 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO Me HI 47 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 H Me HCl 51 SMe 2-H 3-H 5-H 6-H 4 0 H H 1 ^(t)BuOCO H HI 52 SMe 2-H 3-H 5-H 6-H 4 0 H H 1 H H HCl *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 29

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 53 NHNO₂ 2-H 3-H 5-H 6-H 4 0 H H 1 ^(t)BuOCO H — 54 NHNO₂ 2-H 3-H 5-H 6-H 4 0 H H 1 H H — 59 SMe 2-H 4-H 5-H 6-H 3 0 H H 1 ^(t)BuOCO H HI 60 SMe 2-H 4-H 5-H 6-H 3 0 H H 1 H H HCl 61 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 1 ^(t)BuOCO H — 62 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 1 H H HCl 67 SMe 2-H 3-H 5-H 6-H 4 1 COOMe H 0 ^(t)BuOCO H HI 68 SMe 2-H 3-H 5-H 6-H 4 1 COOMe H 0 H H HCl 69 NHNO₂ 2-H 3-H 5-H 6-H 4 1 COOMe H 0 ^(t)BuOCO H — 70 NHNO₂ 2-H 3-H 5-H 6-H 4 1 COOMe H 0 H H — 74 SMe 2-H 3-H 5-H 6-H 4 1 COO′Bu H 0 ^(t)BuOCO H HI 75 SMe 2-H 3-H 5-H 6-H 4 1 COOH H 0 H H HCl 76 NHNO₂ 2-H 3-H 5-H 6-H 4 1 COO′Bu H 0 ^(t)BuOCO H — 77 NHNO₂ 2-H 3-H 5-H 6-H 4 1 COOH H 0 H H HCl 80 SMe 2-H 3-H 5-H 6-H 4 0 COOMe H 0 ^(t)BuOCO H HI *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 30

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 81 SMe 2-H 3-H 5-H 6-H 4 0 COOMe H 0 H H HCl 83 NH^(c)Pr 2-H 3-H 5-H 6-H 4 0 H H 0 ^(t)BuOCO H — 84 NH^(c)Pr 2-H 3-H 5-H 6-H 4 0 H H 0 H H — 85 NHNO₂ 2-H 3-H 5-H 6-H 4 0 H H 0 ^(t)BuOCO H — 86 NHNO₂ 2-H 3-H 5-H 6-H 4 0 H H 0 H H — 87 NH^(c)Pr 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H — 88 NH^(c)Pr 2-H 4-H 5-H 6-H 3 0 H H 0 H H — 89 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 C(═NH)NH^(c)Pr H — 90 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 C(═NH)NHNO₂ H — 91 S^(e)Pr 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H — 92 S^(e)Pr 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 93 S^(e)Bu 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H — 94 S^(e)Bu 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 95 SEt 2-H 4-H 5-H 6-H 3 0 Me Me 0 ^(t)BuOCO H — 96 SEt 2-H 4-H 5-H 6-H 3 0 Me Me 0 H H HCl *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 31

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid  99 NHNO₂ 2-H 3-H 5-H 6-H 4 1 H H 0 Me Me — 101 SMe 2-H 3-H 5-H 6-H 4 1 H H 0 Me Me HNO₃, HCl 102 SEt 2-H 3-H 5-H 6-H 4 1 H H 0 Me Me HNO₃, HCl 103 SEt 2-H 3-H 5-H 6-H 4 1 H H 0 ^(t)BuOCO H — 104 SEt 2-H 3-H 5-H 6-H 4 1 H H 0 H H HCl 109 SMe 2-H 4-H 5-H 6-H 3 0 Me H 0 ^(t)BuOCO Me HI 110 SMe 2-H 4-H 5-H 6-H 3 0 Me H 0 H Me HCl 111 SEt 2-H 4-H 5-H 6-H 3 0 Me H 0 ^(t)BuOCO Me HI 112 SEt 2-H 4-H 5-H 6-H 3 0 Me H 0 H Me HCl 113 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Me H 0 ^(t)BuOCO Me — 114 NHNO₂ 2-H 4-H 5-H 6-H 3 0 Me H 0 H Me — 115 SMe 2-H 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO Me HI 116 SMe 2-H 4-H 5-H 6-H 3 0 H H 0 H Me HCl 121 SEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 ^(t)BuOCO H HI 122 SEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 H H HCl *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 32

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 126 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 CH₃CO H HI 130 SEt 2-Me 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO H HI 131 SEt 2-Me 4-H 5-H 6-H 3 0 H H 0 H H HCl 136 SEt 2-Cl 4-H 5-H 6-H 3 0 H H 0 ^(t)BuOCO ^(t)BuOCO HI 137 SEt 2-Cl 4-H 5-H 6-H 3 0 H H 0 H H HCl 141 SMe 2-H 4-H 5-H 6-H 3 0 —(CH₂)₅— 0 ^(t)BuOCO H — 142 SMe 2-H 4-H 5-H 6-H 3 0 —(CH₂)₅— 0 H H HCl 143 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₅— 0 ^(t)BuOCO H — 144 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₅— 0 H H HCl 145 S^(e)Pr 2-H 4-H 5-H 6-H 3 0 —(CH₂)₅— 0 ^(t)BuOCO H — 146 S^(e)Pr 2-H 4-H 5-H 6-H 3 0 —(CH₂)₅— 0 H H HCl 150 SMe 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 ^(t)BuOCO H — 151 SMe 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 H H HCl 152 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 ^(t)BuOCO H — 153 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 H H HCl *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 33

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 154 S^(e)Pr 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 ^(t)BuOCO H — 155 S^(e)Pr 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 H H HCl 159 SMe 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 ^(t)BuOCO H — 160 SMe 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl 161 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 ^(t)BuOCO H — 162 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl 166 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₂— 0 ^(t)BuOCO H — 167 SEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₂— 0 H H HCl 168 NHNO₂ 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 ^(t)BuOCO H — 169 NHNO₂ 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl 170 NHNO₂ 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 ^(t)BuOCO H — 171 NHNO₂ 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl 172 NHNO₂ 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 ^(t)BuOCO H — 173 NHNO₂ 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl 174 SEt 2-H 4-H 5-H 6-H 3 0 Me H 0 ^(t)BuOCO H — *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 34

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 175 SEt 2-H 4-H 5-H 6-H 3 0 Me H 0 H H HCl 176 SEt 2-H 4-H 5-H 6-H 3 0 Et H 0 ^(t)BuOCO H — 177 SEt 2-H 4-H 5-H 6-H 3 0 Et H 0 H H HCl 184 SEt 2-H 3-H 5-H 6-H 4 0 Me Me 1 ^(t)BuOCO H — 185 SEt 2-H 3-H 5-H 6-H 4 0 Me Me 1 H H HCl 186 NHNO₂ 2-H 3-H 5-H 6-H 4 0 Me Me 1 ^(t)BuOCO H — 187 NHNO₂ 2-H 3-H 5-H 6-H 4 0 Me Me 1 H H HCl 192 SEt 2-H 3-H 5-H 6-H 4 1 Me Me 0 ^(t)BuOCO H — 193 SEt 2-H 3-H 5-H 6-H 4 1 Me Me 0 H H HCl 194 NHNO₂ 2-H 3-H 5-H 6-H 4 1 Me Me 0 ^(t)BuOCO H — 195 NHNO₂ 2-H 3-H 5-H 6-H 4 1 Me Me 0 H H HCl 201 SEt 2-H 4-H 5-H 6-OMe 3 0 H H 0 ^(t)BuOCO H HI 202 SEt 2-H 4-H 5-H 6-OMe 3 0 H H 0 H H HCl 208 SEt 2-H 4-H 5-H 6-Cl 3 0 H H 0 ^(t)BuOCO H HI 209 SEt 2-H 4-H 5-H 6-Cl 3 0 H H 0 H H HCl *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 35

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 211 SMe 2-H 4-H 5-H 6-H 3 0 COOMe H 0 ^(t)BuOCO H — 212 SMe 2-H 4-H 5-H 6-H 3 0 COOMe H 0 H H HCl 216 SMe 2-H 4-H 5-H 6-H 3 1 COOMe H 0 ^(t)BuOCO H — 217 SMe 2-H 4-H 5-H 6-H 3 1 COOMe H 0 H H HCl 220 NHNO₂ 2-H 3-H 5-H 6-H 4 0 COOMe H 1 ^(t)BuOCO H — 221 NHNO₂ 2-H 3-H 5-H 6-H 4 0 COOMe H 1 H H HCl 222 NHNO₂ 2-H 3-H 5-H 6-H 4 0 COOH H 1 ^(t)BuOCO H — 223 NHNO₂ 2-H 3-H 5-H 6-H 4 0 COOH H 1 H H HCl 225 SEt 2-H 3-H 5-H 6-H 4 0 COOMe H 1 ^(t)BuOCO H — 226 SEt 2-H 3-H 5-H 6-H 4 0 COOMe H 1 H H HCl 231 SEt 3-H 4-H 5-H 6-H 2 0 H H 0 ^(t)BuOCO H HI 232 SEt 3-H 4-H 5-H 6-H 2 0 H H 0 H H HCl 234 NHEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl 236 NHEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₄— 0 H H HCl 238 NHEt 2-H 4-H 5-H 6-H 3 0 —(CH₂)₃— 0 H H HCl *Numeral represents the position of substitution on the benzene ring. ★

 

TABLE 36

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 244 SEt 2-H 4-H 5-CF₃ 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 245 SEt 2-H 4-H 5-CF₃ 6-H 3 0 H H 0 H H HCl 246 NHNO₂ 2-H 4-H 5-CF₃ 6-H 3 0 H H 0 ¹ BuOCO ¹BuOCO — 247 NHNO₂ 2-H 4-H 5-CF₃ 6-H 3 0 H H 0 H H HCl 255 SEt 2-H 3-F 5-H 6-H 4 1 H H 0 ¹BuOCO H — 256 SEt 2-H 3-F 5-H 6-H 4 1 H H 0 H H HCl 258 NHEt 2-H 3-F 5-H 6-H 4 1 H H 0 H H HCl 259 NHNO₂ 2-H 3-F 5-H 6-H 4 1 H H 0 ¹BuOCO H — 260 NHNO₂ 2-H 3-F 5-H 6-H 4 1 H H 0 H H HCl 267 NHEt 2-H 4-NMe₂ 5-H 6-H 3 0 H H 0 H H HCl 269 SEt 2-H 4-NMe₂ 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 270 SEt 2-H 4-NMe₂ 5-H 6-H 3 0 H H 0 H H HCl 271 NHNO₂ 2-H 4-OMe 5-H 6-H 3 0 H H 0 ¹BuOCO H — 272 NHNO₂ 2-H 4-OMe 5-H 6-H 3 0 H H 0 H H HCl 274 NHEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 37

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 275 NHMe 2-H 4-OMe 5-H 6-H 3 0 H H 0 ¹BuOCO H — 276 NHMe 2-H 4-OMe 5-H 6-H 3 0 H H 0 H H HCl 278 NH*Pr 2-H 4-OMe 5-H 6-H 3 0 H H 0 ¹BuOCO H — 279 NH*Pr 2-H 4-OMe 5-H 6-H 3 0 H H 0 H H HCl 280 NHNO₃ 2-H 4-NMe₃ 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 281 NHNO₃ 2-H 4-NMe₃ 5-H 6-H 3 0 H n 0 H H HCl 285 NHEt 2-H 4-NMeEt 5-H 6-H 3 0 H H 0 H H HCl 287 SEt 2-H 4-NMeEt 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 288 SEt 2-H 4-NMeEt 5-H 6-H 3 0 H H 0 H H HCl 291 NHOMe 2-H 3-H 5-H 6-H 4 1 H H 0 H H HCl 297 SEt 2-OMe 4-OMe 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 298 SEt 2-OMe 4-OMe 5-H 6-H 3 0 H H 0 H H HCl 300 NHEt 2-H 4-H 5-H 6-H 3 0 Me Me 0 H H HCl 302 NMe₂ 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 303 NMe₂ 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 38

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 304 NMeEt 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 305 NMeEt 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 306 NHCH₂C≡CH 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 307 NHCH₂C≡CH 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 312 SEt 3-H 4-H 5-H 6-H 2 1 H H 0 ¹BuOCO H — 313 SEt 3-H 4-H 5-H 6-H 2 1 H H 0 H H HCl 316 SEt 2-H 4-F 5-H 6-H 3 0 H H 0 ¹BuOCO H — 317 SEt 2-H 4-F 5-H 6-H 3 0 H H 0 H H HCl 323 SEt 2-H 4-OEt 5-H 6-H 3 0 H H 0 ¹BuOCO H HI 324 SEt 2-H 4-OEt 5-H 6-H 3 0 H H 0 H H HCl 326 NHEt 2-H 4-OEt 5-H 6-H 3 0 H H 0 H H HCl 327 NHNO₃ 2-H 4-OEt 5-H 6-H 3 0 H H 0 ¹BuOCO H — 328 NHNO₃ 2-H 4-OEt 5-H 6-H 3 0 H H 0 H H HCl 336 SEt 2-H 4-OBn 5-H 6-H 3 0 H H 0 ¹BuOCO H — 337 SEt 2-H 4-OBn 5-H 6-H 3 0 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 39

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 339 NHEt 2-H 4-OBn 5-H 6-H 3 0 H H 0 H H HCl 340 NHNO₂ 2-H 4-OBn 5-H 6-H 3 0 H H 0 ¹BuOCO H — 341 NHNO₂ 2-H 4-OBn 5-H 6-H 3 0 H H 0 H H HCl 342 SEt 2-H 4-OMe 5-H 6-H 3 0 Me Me 0 ¹BuOCO H HI 350 SEt 2-H 4-OMe 5-H 6-H 3 0 Me Me 0 H H HCl 354 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCONH HI 355 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 H NH₂ HCl 356 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCONH — 357 NHNO₂ 2-H 4-H 5-H 6-H 3 0 H H 0 H NH₂ HCl 360 NHNO₂ 2-H 3-H 5-H 6-H 4 1 H H 1 ¹BuOCO H — 361 NHNO₂ 2-H 3-H 5-H 6-H 4 1 H H 1 H H HCl 365 SMe 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO HI 366 NHMe 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 367 NHMe 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 368 NHEt 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 40

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 369 NHEt 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 370 NH*Pr 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 371 NH*Pr 2-H 4-H 5-H 6-H 3 0 H H 0 H H HCl 372 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 Me Me — 374 NHEt 2-H 4-H 5-H 6-H 3 0 H H 0 Me Me HCl 376 NHEt 2-H 4-H 5-H 6-H 3 0 H H 0 Me H HCl 380 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 Bn Me HCl 382 NHEt 2-H 4-H 5-H 6-H 3 0 H H 0 Bn Me HCl 387 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO Et HI 388 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 H Et HCl 392 NHEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 Me H HCl 394 SEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 ¹BuOCO Me HI 395 SEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 H Me HCl 399 NHEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 Me Me HCl 401 SEt 2-H 4-OMe 5-H 6-H 3 0 H H 0 Me Me HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 41

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 405 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO Bn HI 406 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 H Bn HCl 410 SEt 2-Me 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO Me HI 411 SEt 2-Me 4-H 5-H 6-H 3 0 H H 0 H Me HCl 413 NHEt 2-Me 4-H 5-H 6-H 3 0 H H 0 H Me HCl 415 SEt 2-Me 4-H 5-H 6-H 3 0 H H 0 Me Me HCl 417 NHEt 2-Me 4-H 5-H 6-H 3 0 H H 0 Me Me HCl 423 SEt 2-OMe 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO H — 424 SEt 2-OMe 4-H 5-H 6-H 3 0 H H 0 H H HCl 426 NHEt 2-OMe 4-H 5-H 6-H 3 0 H H 0 H H HCl 430 SEt 2-H 4-H 5-Me 6-H 3 0 H H 0 ¹BuOCO H — 431 SEt 2-H 4-H 5-Me 6-H 3 0 H H 0 H H HCl 433 NHEt 2-H 4-H 5-Me 6-H 3 0 H H 0 H H HCl 437 SEt 2-H 4-NHBn 5-H 6-H 3 0 H H 0 ¹BuOCO H — 438 SEt 2-H 4-NHBn 5-H 6-H 3 0 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 42

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 440 NHEt 2-H 4-NHBn 5-H 6-H 3 0 H H 0 H H HCl 442 NHEt 3-H 4-H 5-H 6-H 2 1 H H 0 ¹BuOCO H — 443 NHEt 3-H 3-H 5-H 6-H 2 1 H H 0 H H HCl 445 NHEt 2-H 4-F 5-H 6-H 3 0 H H 0 H H HCl 449 NHEt 2-H 4-NHMe 5-H 6-H 3 0 H H 0 H H HCl 451 SEt 2-H 4-NHMe 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 452 SEt 2-H 4-NHMe 5-H 6-H 3 0 H H 0 H H HCl 456 NHEt 2-H 4-NHEt 5-H 6-H 3 0 H H 0 H H HCl 458 SEt 2-H 4-NHEt 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 459 SEt 2-H 4-NHEt 5-H 6-H 3 0 H H 0 H H HCl 463 SEt 2-H 4-Et 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 464 SEt 2-H 4-Et 5-H 6-H 3 0 H H 0 H H HCl 466 NHEt 2-H 4-Et 5-H 6-H 3 0 H H 0 H H HCl 470 SEt 2-H 4-Me 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 471 SEt 2-H 4-Me 5-H 6-H 3 0 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 43

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 473 NHEt 2-H 4-Me 5-H 6-H 3 0 H H 0 H H HCl 481 SEt 2-H 3-OMe 5-H 6-H 4 1 H H 0 ¹BuOCO H — 482 SEt 2-H 3-OMe 5-H 6-H 4 1 H H 0 H H HCl 484 NHEt 2-H 3-OMe 5-H 6-H 4 1 H H 0 H H HCl 492 SEt 2-OMe 3-H 5-H 6-H 4 1 H H 0 ¹BuOCO H — 493 SEt 2-OMe 3-H 5-H 6-H 4 1 H H 0 H H HCl 497 SEt 2-Cl 3-H 5-H 6-H 4 1 H H 0 ¹BuOCO H — 498 SEt 2-Cl 3-H 5-H 6-H 4 1 H H 0 H H HCl 506 SEt 2-F 3-H 5-H 6-H 4 1 H H 0 ¹BuOCO H 507 SEt 2-F 3-H 5-H 6-H 4 1 H H 0 H H HCl 512 SEt 3-H 4-OMe 5-H 6-H 2 1 H H 0 ¹BuOCO H — 513 SEt 3-H 4-OMe 5-H 6-H 2 1 H H 0 H H HCl 514 NHNO₂ 3-H 4-OMe 5-H 6-H 2 1 H H 0 ¹BuOCO H — 515 NHNO₂ 3-H 4-OMe 5-H 6-H 2 1 H H 0 H H HCl 517 NHEt 3-H 4-OMe 5-H 6-H 2 1 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 44

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 525 SEt 2-Me 3-H 5-H 6-H 4 1 H H 0 ¹BuOCO H — 526 SEt 2-Me 3-H 5-H 6-H 4 1 H H 0 H H HCl 528 NHEt 2-H 3-H 5-H 6-H 4 1 H H 0 H H HCl 532 NHEt 2-Me 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 533 NHEt 2-Me 4-H 5-H 6-H 3 0 H H 0 H H HCl 534 NMeEt 2-Me 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 535 NMeEt 2-Me 4-H 5-H 6-H 3 0 H H 0 H H HCl 537 NMeEt 2-Cl 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 538 NHEt 2-Cl 4-H 5-H 6-H 3 0 H H 0 H H HCl 539 NMeEt 2-Cl 4-H 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 540 NMeEt 2-Cl 4-H 5-H 6-H 3 0 H H 0 H H HCl 542 NHEt 2-H 4-H 5-H 6-H 3 1 H H 0 ¹BuOCO H — 543 NHEt 2-H 4-H 5-H 6-H 3 1 H H 0 H H HCl 544 NMeEt 2-H 4-H 5-H 6-H 3 1 H H 0 ¹BuOCO H — 545 NMeEt 2-H 4-H 5-H 6-H 3 1 H H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 45

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 549 SEt 2-H 4-pipelidino 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 550 SEt 2-H 4-pipelidino 5-H 6-H 3 0 H H 0 H H HCl 552 NHEt 2-H 4-pipelidino 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 553 NHEt 2-H 4-pipelidino 5-H 6-H 3 0 H H 0 H H HCl 557 SEt 2-H 4-Cl 5-H 6-H 3 0 H H 0 ¹BuOCO H — 558 SEt 2-H 4-Cl 5-H 6-H 3 0 H H 0 H H HCl 560 NHEt 2-H 4-Cl 5-H 6-H 3 0 H H 0 H H HCl 567 NHNO₂ 2-H 4-OBn 5-H 6-H 3 0 Me Me 0 ¹BuOCO H — 568 NHNO₂ 2-H 4-OBn 5-H 6-H 3 0 Me Me 0 H H — 570 NHEt 2-H 4-OBn 5-H 6-H 3 0 Me Me 0 H H — 572 SEt 2-H 4-OBn 5-H 6-H 3 0 Me Me 0 ¹BuOCO H — 573 SEt 2-H 4-OBn 5-H 6-H 3 0 Me Me 0 H H — 580 NHEt 2-OBn 4-H 5-H 6-H 3 0 Me Me 0 H H — 582 SEt 2-OBn 4-H 5-H 6-H 3 0 Me Me 0 ¹BuOCO H — 583 SEt 2-OBn 4-H 5-H 6-H 3 0 Me Me 0 H H — *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 46

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 587 SEt 2-H 4-pyrrolidinyl 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 588 SEt 2-H 4-pyrrolidinyl 5-H 6-H 3 0 H H 0 H H HCl 590 NHEt 2-H 4-pyrrolidinyl 5-H 6-H 3 0 H H 0 H H HCl 592 NHEt 2-OMe 3-H 5-H 6-H 4 1 H H 0 H H HCl 594 NHEt 2-Cl 3-H 5-H 6-H 4 1 H H 0 H H HCl 596 NHEt 2-F 3-H 5-H 6-H 4 1 H H 0 H H HCl 598 NHEt 2-H 4-H 5-H 6-H 3 0 Me H 0 H H HCl 600 NHEt 2-Me 3-H 5-H 6-H 4 1 H H 0 H H HCl 607 SEt 2-H 3-Cl 5-H 6-H 4 1 H H 0 ¹BuOCO H — 608 SEt 2-H 3-Cl 5-H 6-H 4 1 H H 0 H H HCl 610 NHEt 2-H 3-Cl 5-H 6-H 4 1 H H 0 H H HCl 614 SEt 2-H 4-NMeBn 5-H 6-H 3 0 H H 0 H H HCl 616 NHEt 2-H 4-NMeBn 5-H 6-H 3 0 H H 0 H H HCl 621 SEt 2-Me 4-H 5-H 6-H 3 0 Me H 0 ¹BuOCO H — 622 SEt 2-Me 4-H 5-H 6-H 3 0 Me H 0 H H HCl *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 47

Example Z★ No. R₁ Y₁* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 624 NHEt 2-Me 4-H 5-H 6-H 3 0 Me H 0 H H HCl 626 SEt 2-H 3-H 5-H 6-H 4 0 H H 0 PhCO H — 628 NHEt 2-H 3-H 5-H 6-H 4 0 H H 0 PhCO H — 631 SEt 2-H 4-H 5-H 6-H 3 0 H H 0 PhCO H — 633 NHEt 2-H 4-H 5-H 6-H 3 0 H H 0 PhCO H HCl 638 SEt 2-H 4-OMe 5-H 6-H 3 0 Me H 0 ¹BuOCO H — 639 SEt 2-H 4-OMe 5-H 6-H 3 0 Me H 0 H H HCl 641 NHEt 2-H 4-OMe 5-H 6-H 3 0 Me H 0 H H HCl 645 SEt 2-H 4-NMeAc 5-H 6-H 3 0 H H 0 ¹BuOCO ¹BuOCO — 646 SEt 2-H 4-NMeAc 5-H 6-H 3 0 H H 0 H H HCl 648 NHEt 2-H 4-NMeAc 5-H 6-H 3 0 H H 0 H H HCl 654 NHEt 2-NMe₂ 4-H 5-H 6-H 3 0 H H 0 H H HCl 656 NHEt 2-H 4-OH 5-H 6-H 3 0 H H 0 H H HCl 657 SEt 2-H 4-NHAc 5-H 6-H 3 0 H H 0 H H — 658 NHEt 2-H 4-NHAc 5-H 6-H 3 0 H H 0 H H — *: Numeral represents the position of substitution on the benzene ring.

 

TABLE 48

Example Z★ No. R₁ Y₂* Y₂* Y₃* Y₄* position n R₂ R₃ m R₄ R₅ Acid 659 SEt 2-H 4-NHBz 5-H 6-H 3 0 H H 0 H H — 660 NHEt 2-H 4-NHBz 5-H 6-H 3 0 H H 0 H H — 661 SEt 3-H 4-NMeBz 5-H 6-H 3 0 H H 0 H H — 662 NHEt 3-H 4-NMeBz 5-H 6-H 3 0 H H 0 H H — 663 SEt 2-F 4-H 5-H 6-H 3 0 H H 0 H H — 664 NHEt 2-F 4-H 5-H 6-H 3 0 H H 0 H H — *: Numeral represents the position of substitution on the benzene ring.

 

Example 1 Synthesis of N-(1-methyl-1-(3-nitrophenyl)ethyl)carbamic acid t-butyl ester Example 1a

A solution of 3-nitrophenylacetic acid t-butyl ester (1.56 g) in dimethylformamide (30 ml) was added dropwise to a mixture of sodium hydride (content=60%; 631 mg) and dimethylformamide (45 ml) at 0° C. After the reaction mixture was stirred for 10 min, methyl iodide (2 eq., 0.9 ml) was added dropwise at 0 ° C., and stirred for 30 min and stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=97:3) to give 367 mg of 2-methyl-2-(3-nitrophenyl)propionic acid t-butyl ester (yield, 28%).

¹H-NMR(CDCl₃) δ: 1.39(9H,s), 1.59(6H,s), 7.46-7.69(2H,m), 8.08-8.25(2H,m)

Example 1b

A mixture of the dimethyl compound (1.1 g) obtained in the above reaction and trifluoroacetic acid (25 ml) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:6) to give 0.87 g of 2-methyl-2-(3-nitrophenyl)propionic acid quantitatively. ¹H-NMR(CDCl₃) δ: 1.67(6H,s), 7.52-7.76(2H,m), 8.12-8.29(2H,m)

Example 1c

A mixture of 2-methyl-2-(3-nitrophenyl)-propionic acid (866 mg) obtained in Example 1b, diphenylphosphorylazide (0.89 ml), triethylamine (0.58 ml) and t-butanol (15 ml) was refluxed for 16 h and concentrated under reduced pressure. The residue was dissolved in benzene and washed successively with a 5% aqueous citric acid solution, water, a saturated aqueous sodium chloride solution and a saturated aqueous sodium bicarbonate solution; the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=85:15) to yield 649 mg of the titled compound (yield, 56%).

¹H-NMR(CDCl₃) δ: 1.38(9H,s), 1.65(6H,s), 5.08(1H,brs), 7.46-7.75(2H,m), 8.07-8.28(2H,m)

MS(m/z) 280(M⁺)

Example 2 Synthesis of N-(1-methyl-1-(3-aminophenyl)ethyl)carbamic acid t-butyl ester

A mixture of the compound (649 mg) obtained in Example 1, 10% palladium-carbon (300 mg) and ethanol (100 ml) was stirred in a hydrogen atmosphere at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=7:3) to give 439 mg of the titled compound (yield, 76%).

H-NMR(CDCl₃) δ: 1.37(9H,s), 1.60(6H,s), 3.62(2H,brs), 4.87(1H, brs), 6.53-6.81(3H,m), 7.07-7.13(1H,m)

MS(m/z)250(M⁺)

Example 3 Synthesis of N-(1-methyl-1-(3-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Thiophosgene (0.12 ml) and a solution of the compound (284 mg) obtained in Example 2 in methylene chloride (10 ml) were added dropwise to a suspension of calcium carbonate (319 mg) in water (5 ml) at room temperature and stirred at room temperature for 5 h; thereafter, a 28% aqueous ammonia solution (5 ml) was added to the reaction mixture and stirred at room temperature for 16 h. After neutralization with 2 N HCl, the reaction mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to yield 351 mg of the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 1.60(6H,s), 5.04(1H,brs), 6.21(2H,brs), 7.05-7.42(4H,m), 8.07(1H,brs)

MS(m/z)309(M⁺)

Example 4 Synthesis of N-(1-methyl-1-(3-(S-methylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester hydroiodide

To a mixture of the compound (164 mg) obtained in Example 3 and acetonitrile (15 ml) was added methyl iodide (0.1 ml) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=95:5) to give 130 mg of the titled compound (yield, 54%).

¹H-NMR(CDCl₃) δ: 1.37(9H,s), 1.60(6H,s), 2.47(3H,s), 4.93(1H,brs), 6.77-7.29(4H,m)

Example 5 Syntheis of N-(1-methyl-1-(3-(S-methylisothioureido)phenyl)ethyl)amine dihydrochloride

A mixture of the compound (130 mg) obtained in Example 4 and trifluoroacetic acid (15 ml) was stirred at room temperature for 2 h, and concentrated under reduced pressure. The residue was dissolved in ethanol (5 ml) and, thereafter, a solution of hydrogen chloride in 1,4-dioxane (4N, 0.29 ml) was added at room temperature and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate and freeze-dried to give 100 mg of the titled compound (yield, 84%).

¹H-NMR(D₂O) δ: 1.77(6H,s), 2.70(3H,s), 7.40-7.68(4H,m)

MS(m/z) 223(M⁺)

Example 6 Synthesis of N-(1-methyl-1-(3-(N′-nitroguanidino)phenyl)ethyl)carbamic acid t-butyl ester

A mixture of the compound (145 mg) obtained in Example 2, acetonitrile (10 ml), N-methyl-N′-nitro-N-nitrosoguanidine (85 mg), triethylamine (0.08 ml) and acetic acid (0.03 ml) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 106 mg of the titled compound (yield, 54%).

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 1.62(6H,s), 5.06(1H,brs), 7.16-7.47(4H,m), 9.73(1H,brs)

FAB-MS(m/z) 338(M⁺+1)

Example 7 Synthesis of N-(1-methyl-1-(3-(N′-nitroguanidino)phenyl)ethyl)amine hydrochloride

Using the compound obtained in Example 6 as a starting material, the same procedure of Example 5 gave 66 mg of the titled compound (yield, 77%).

¹H-NMR(D₂O) δ: 1.76(6H,s), 7.37-7.62(4H,m)

FAB-MS(m/z) 238(M⁺+1)

Example 8 Synthesis of N-(1-(3-nitrophenyl)ethyl)carbamic acid t-butyl ester Example 8a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and methyl iodide (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-(3-nitrophenyl)propionic acid.

¹H-NMR(CDCl₃) δ: 1.59(3H,d, J=7.3 Hz), 3.88(1H,q, J=7.3 Hz), 7.49-7.68(2H,m), 8.13-8.21(2H,m)

Example 8b

Using 2-(3-nitrophenyl)propionic acid as a starting material, the same procedure of Example 1c gave 183 mg of the titled compound (yield, 67%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 1.48(3H,d, J=6.6 Hz), 4.68-5.06(2H,m), 7.47-7.66(2H,m), 8.10-8.17(2H,m)

MS(m/z) 266(M⁺)

Example 9 Synthesis of N-(1-(3-aminophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 8 as a starting material, the same procedure of Example 2 gave 496 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.40-1.42(12H,m), 3.66(2H,brs), 4.58-4.86(2H,m), 6.55-6.70(3H,m), 7.08-7.14(1H,m)

Example 10 Synthesis of N-(1-(3-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 9 as a starting material, the same procedure of Example 3 gave 246 mg of the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 1.43(3H,d J=6.9 Hz), 4.67-4.79(1H,m) 4.80-4.98(1H,m), 6.14(2H,brs), 7.09-7.43(4H,m), 7.97(1H,brs)

Example 11 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 10 as a starting material, the same procedure of Example 4 gave 318 mg of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.42-1.45(12H,m), 2.60(3H,s), 4.68-4.91(2H,m), 7.03-7.37(4H,m)

Example 12 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 11 as a starting material, the same procedure of Example 5 gave 192 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.67(3H,d, J=6.9 Hz), 2.70(3H,s), 4.61(1H,q, J=6.9 Hz), 7.42-7.67(4H,m)

MS(m/z) 209(M⁺)

Example 13 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 9 as a starting material, the same procedure of Example 6 gave 123 mg of the titled compound (yield, 40%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 1.46(3H,d, J=6.9 Hz), 4.72-4.80(1H,m), 4.89(1H,d, J=6.3 Hz), 7.17-7.49(4H,m), 9.25(1H,brs)

FAB-MS(m/z) 324(M⁺+1)

Example 14 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)ethyl)amine hydrochloride

Using the compound obtained in Example 13 as a starting material, the same procedure of Example 7 gave 92 mg of the titled compound (yield, 84%).

¹H-NMR(D₂O) δ: 1.66(3H,d, J=6.9 Hz), 4.58(1H,q, J=6.9 Hz), 7.38-7.61(4H,m)

FAB-MS(m/z) 224(M⁺+1)

Example 15 Synthesis of N-(1-(3-nitrophenyl)propyl)carbamic acid t-butyl ester Example 15a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using ethyl iodide (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-(3-nitrophenyl)butyric acid.

¹H-NMR(CDCl₃) δ: 0.94(3H,t, J=7.3 Hz), 1.79-1.95(1H,m), 2.10-2.26(1H,m), 3.60(1H,t, J=7.6 Hz), 7.49-7.78(2H,m), 8.13-8.28(2H,m)

Example 15b

Using 2-(3-nitrophenyl)butyric acid as a starting material, the same procedure of Example 1c gave 1.0 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 0.93(3H,t, J=7.3 Hz), 1.42(9H,s), 1.73-1.84(2H,m), 4.51-4.71(1H,m), 4.78-4.98(1H,m), 7.47-7.67(2H,m), 8.10-8.13 (2H,m)

Example 16 Synthesis of N-(1-(3-aminophenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 15 as a starting material, the same procedure of Example 2 gave 701 mg of the titled compound (yield, 79%).

¹H-NMR(CDCl₃) δ: 0.87(3H,t, J=7.3 Hz), 1.41(9H,s), 1.68-1.85(2H,m), 3.64(2H, brs), 4.30-4.50(1H,m), 4.62-4.86(1H,m), 6.55-6.66(3H,m), 7.07-7.13(1H,m)

Example 17 Synthesis of N-(1-(3-thioureidophenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 16 as a starting material, the same procedure of Example 3 gave 371 mg of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 0.92(3H,t, J=7.3 Hz), 1.40(9H,s), 1.69-1.80(2H,m), 4.40-4.60(1H,m), 4.80-5.00(1H,m), 6.15(2H,brs), 7.09-7.42 (4H,m), 7.97(1H,brs)

Example 18 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)propyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 17 as a starting material, the same procedure of Example 4 gave 443 mg of the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 0.90(3H,t, J=7.3 Hz), 1.41(9H,s), 1.70-1.80(2H,m), 2.59(3H,s), 4.39-4.61(1H,m), 4.85(1H,d, J=7.6 Hz), 7.01-7.36(4H,m)

Example 19 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)propyl)amine dihydrochloride

Using the compound obtained in Example 18 as a starting material, the same procedure of Example 5 gave 267 mg of the titled compound (yield, 93%).

¹H-NMR(D₂O) δ: 0.89(3H,t, J=7.3 Hz), 1.91-2.16(2H,m), 2.70(3H,s), 4.30-4.36(1H,m), 7.43-7.70(4H,m)

MS(m/z) 223(M⁺)

Example 20 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 16 as a starting material, the same procedure of Example 6 gave 406 mg of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 0.94(3H,t, J=7.3 Hz), 1.40(9H,s), 1.72-1.83(2H,m), 4.43-4.58(1H,m), 4.84-5.01(1H,m), 7.19-7.48(4H,m), 9.56(1H,brs)

FAB-MS(m/z) 338(M⁺+1)

Example 21 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)propyl)amine hydrochloride

Using the compound obtained in Example 20 as a starting material, the same procedure of Example 5 gave 270 mg of the titled compound (yield, 83%). ¹H-NMR(D₂O) δ: 0.89(3H,t, J=7.3 Hz), 1.93-2.12(2H,m), 4.30(1H,t, J=8.6 Hz), 7.39-7.61(4H,m)

FAB-MS(m/z) 238(M⁺+1)

Example 22 Synthesis of N-(3-nitrophenylmethyl)carbamic acid t-butyl ester

Triethylamine (2.8 ml) and di-t-butyl dicarbonate (2.3 g) were added to a solution of 3-nitrobenzylamine hydrochloride (1.5 g) in dimethylformamide (30 ml) and stirred at room temperature for 16 h. Water and 2 N HCl were added to the reaction mixture for pH adjustment to 3; following extraction with ethyl acetate, the organic layer was successively washed with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 1.9 g of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 4.42(2H,d, J=6.3 Hz), 4.92-5.10(1H,m), 7.48-7.65(2H,m), 8.11-8.15(2H,m)

Example 23 Synthesis of N-(3-aminophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 22 as a starting material, the same procedure of Example 2 gave 1.1 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 3.66(2H,brs), 4.21(2H,d, J=5.9 Hz), 4.73-4.87(1H,m), 6.56-6.67(3H,m), 7.07-7.13(1H,m)

Example 24 Synthesis of N-(3-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 23 as a starting material, the same procedure of Example 3 gave 382 mg of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 4.32(2H,d, J=5.9 Hz), 4.97-5.11(1H,m), 6.22(2H,brs), 7.12-7.27(3H,m), 7.36-7.42(1H,m), 8.19(1H,brs)

FAB-MS(m/z) 282(M⁺+1)

Example 25 Synthesis of N-(3-(S-methylisothioureido)phenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 24 as a starting material, the same procedure of Example 4 gave 489 mg of the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 2.46(3H,s), 4.28(2H,d, J=5.6 Hz), 4.75-4.89(1H,m), 6.81-6.97(3H,m), 7.24-7.29(1H,m)

FAB-MS(m/z) 296(M⁺+1)

Example 26 Synthesis of N-(3-(S-methylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 25 as a starting material, the same procedure of Example 5 gave 150 mg of the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 2.70(3H,s), 4.25(2H,s), 7.31-7.66(4H,m)

FAB-MS(m/z) 196(M⁺+1)

Example 27 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 24 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 4 gave 178 mg of the titled compound (yield, 68%).

¹H-NMR(CDCl₃) δ: 1.37(3H,t, J=7.3 Hz), 1.46(9H,s), 3.06(2H,q, J=7.3 Hz), 4.29(2H, d, J=5.9 Hz), 4.78-4.92(1H,m), 6.87-7.31(4H,m)

Example 28 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 27 as a starting material, the same procedure of Example 5 gave 105 mg of the titled compound (yield, 92%).

¹H-NMR(D₂O) δ: 1.43(3H,t, J=7.3 Hz), 3.25(2H,q, J=7.3 Hz), 4.25(2H,s), 7.43-7.66(4H,m)

MS(m/z) 209(M⁺)

Example 29 Synthesis of N-(3-(S-(2-fluoroethyl)isothioureido)phenylmethyl)carbamic acid t-butyl ester

To a mixture of the compound (500 mg) obtained in Example 24 and acetonitrile (20 ml) was added 1-bromo-2-fluoroethane (0.26 ml) and the reaction mixture was heated under reflux for 2 h. The reaction mixture was distilled under reduced pressure and the resulting residue was dissolved in ethyl acetate and washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and the organic layer was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 50 mg of the titled compound (yield, 9%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 3.36(2H, destorted dt, J=22.1, 5.9 Hz), 4.27(2H, d, J=5.6 Hz), 4.66(2H, destorted dt, J=47.2, 5.9 Hz), 4.80-4.94(1H,m), 6.77-6.97(3H,m), 7.24-7.29(1H,m)

Example 30 Synthesis of N-(3-(S-(2-fluoroethyl)isothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 29 as a starting material, the same procedure of Example 5 gave 36 mg of the titled compound (yield, 79%).

¹H-NMR(D₂O) δ: 3.61(2H, destorted dt, J=25.4, 5.3 Hz), 4.24(2H,s), 4.82(2H,destorted dt, J=46.5, 5.3 Hz), 7.41-7.71(4H,m)

Example 31 Synthesis of N-(3-(S-(2-propenyl)isothioureido)phenylmethyl)carbamic acid t-butyl ester hydrobromide

Using the compound obtained in Example 24 as a starting material and also using allyl bromide as a reagent, the same procedure of Example 4 gave 118 mg of the titled compound (yield, 34%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 3.85(2H,d, J=6.6 Hz), 4.30(2H, d, J=5.9 Hz), 4.93-5.05(1H,m), 5.28(1H,d, J=9.9 Hz), 5.44(1H,d, J=16.8 Hz), 5.83-5.98(1H,m), 7.03-7.36(4H,m)

MS(m/z) 321(M⁺)

Example 32 Synthesis of N-(3-(S-(2-propenyl)isothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 31 as a starting material, the same procedure of Example 5 gave 73 mg of the titled compound (yield, 85%).

¹H-NMR(D₂O) δ: 3.91(2H,d, J=6.6 Hz), 4.24(2H,s), 5.36(1H,d, J=10.2 Hz), 5.44(1H,d, J=16.8 Hz), 5.93-6.08(1H,m), 7.42-7.66(4H,m)

MS(m/z) 221(M⁺)

Example 33 Synthesis of N-(3-(N′-nitroguanidino)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 23 as a starting material, the same procedure of Example 6 gave 201 mg of the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 4.33(2H,d, J=6.3 Hz), 4.86-5.00(1H,m), 6.55(1H,brs), 7.17-7.47(4H,m), 9.03(1H,brs)

FAB-MS(m/z) 310(M⁺+1)

Example 34 Synthesis of N-(3-(N′-nitroguanidino)phenylmethyl)amine

A mixture of the compound (230 mg) obtained in Example 33, methylene chloride (3 ml) and trifluoroacetic acid (1.15 ml) was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and 25% aqueous ammonia solution was added to the resulting residue, and the reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; methanol) to give 117 mg of the titled compound (yield, 75%).

¹H-NMR(CDCl₃) δ: 4.14(2H,s), 7.30-7.34(2H,m), 7.45(1H,d, J=7.9 Hz), 7.56(1H,s)

Example 35 Synthesis of N-(3-guanidinophenylmethyl)carbamic acid t-butyl ester formate

A solution of the compound (190 mg) obtained in Example 33 in 4.4% formic acid-methanol (10 ml) was added dropwise to a suspension of palladium-black (200 mg) in 4.4% formic acid-methanol (10 ml) at room temperature and stirred at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=8:2) to give 71 mg of the titled compound (yield, 37%).

¹H-NMR(CDCl₃) δ: 1.39(9H,s), 4.22(2H, d, J=5.9 Hz), 5.59-5.76(1H,m), 7.05-7.36(4H,m), 9.72(1H,brs)

FAB-MS(m/z) 265(M⁺+1)

Example 36 Synthesis of N-(3-guanidinophenylmethyl)amine dihydrochloride

Using the compound obtained in Example 35 as a starting material, the same procedure of Example 5 gave 57 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 4.22(2H,s), 7.35-7.60(4H,m)

FAB-MS(m/z) 165(M⁺+1)

Example 37 Synthesis of N-(3-nitrophenylmethyl)dimethylamine

A solution of m-nitro-α-bromotoluene (3.2 g) in dimethylformamide (50 ml) was added dropwise to a solution of dimethylamine hydrochloride (1.45 g) and triethylamine (4.36 ml) in dimethylformamide (50 ml). The reaction mixture was stirred at room temperature for 1 h and then its temperature was raised to 50° C., at which it was stirred for 3 h. The reaction mixture was distilled under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 2.56 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 2.26(6H,s), 3.15(2H,s), 7.49(1H,dd, J=7.9, 7.6 Hz), 7.67(1H,d, J=7.6 Hz), 8.12(1H,d, J=7.9 Hz), 8.19(1H,s)

Example 38 Synthesis of N-(3-aminophenylmethyl)dimethylamine

Using the compound obtained in Example 37 as a starting material, the same procedure of Example 2 gave 1.6 g of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 2.24(6H,s), 3.37(2H,s), 3.45(2H,brs), 6.58(1H,d, J=6.6 Hz), 6.66-6.69(2H,m), 7.10(1H, dd, J=7.6, 6.6 Hz)

Example 39 Synthesis of N-(3-(N′-nitroguanidino)phenylmethyl)dimethylamine acetate

Using the compound obtained in Example 38 as a starting material, the same procedure of Example 6 gave 0.11 g of the titled compound (yield, 42%).

¹H-NMR(DMSO-d₆) δ: 2.13(3H,s), 2.16(6H,s), 3.37(2H,s), 7.08(1H, d, J=7.3 Hz), 7.22-7.30(3H,m), 8.26-8.80(1H,m)

MS(m/z) 191(M⁺−46)

Example 40 Synthesis of N-(3-thioureidophenylmethyl)dimethylamine

Benzoyl chloride (0.18 ml) was added to a solution of ammonium thiocyanate (0.12 g) in acetone (7 ml) and heated under reflux for 5 min. Subsequently, a solution of the compound (0.21 g) obtained in Example 38 in acetone (6 ml) was added. The reaction mixture was stirred at room temperature for 20 min and then water was added to give a yellow precipitate, which was separated off by filtration. To the recovered product, 10% aqueous sodium hydroxide solution (20 ml) was added and heated under reflux for 5 min. The reaction mixture was made acidic with 35% HCl, then weakly alkaline with 28% aqueous ammonia solution, and concentrated to 20 ml under reduced pressure. The resulting precipitate was filtered off and the filtrate was extracted with chloroform; the organic layer was dried with anhydrous magnesium sulfate and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, chloroform methanol=5:1) to give 0.1 g of the titled compound (yield, 35%).

¹H-NMR(DMSO-d₆) δ: 2.22(6H,s), 3.49(2H,s), 6.72(2H,brs), 7.15-7.36(4H,m), 9.12(1H,brs)

MS(m/z) 209(M⁺)

Example 41 Synthesis of N-(3-(S-methylisothioureido)phenylmethyl)dimethylamine mononitrate monohydrochloride

To a mixture of the compound (42.7 mg) obtained in Example 40 and tetrahydrofuran (2 ml), 60% nitric acid (0.1 ml) was added and the resulting mixture was concentrated under reduced pressure to form a nitrate, which was subjected to the same reaction as in Example 4; the residue was dissolved in ethanol (1 ml) and a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml) was added at room temperature; then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate and freeze-dried to give 46.9 mg of the titled compound (yield, 71%).

¹H-NMR(DMSO-d₆) δ: 2.34(6H,s), 2.42(3H,s), 3.54(2H,s), 4.45(3H,br), 6.86(1H,d, J=7.9 Hz), 6.92(1H,s), 6.99(1H,d, J=7.6 Hz), 7.25(1H, dd, J=7.9, 7.6 Hz), 7.69(1H,s)

MS(m/z) 223(M⁺)

Example 42 Synthesis of N-(3-nitrophenylmethyl)methylamine

To a mixture of sodium cyanoborohydride (2.52 g), triethylamine (18.7 ml), methylamine hydrochloride (5.42 g) and methanol (660 ml), m-nitrobenzaldehyde (10.10 g) was added dropwise over 20 minutes at room temperature and the resulting mixture was stirred at room temperature for 20 h. The pH of the reaction mixture was adjusted to 2 by addition of 10% HCl and the methanol was distilled off under reduced pressure. The residue was washed with chloroform and a 10% aqueous potassium hydroxide solution was added to the aqueous layer for pH adjustment to 12, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=95:5) to give 3.0 g of the titled compound (yield, 27%).

¹H-NMR(CDCl₃) δ: 1.52(1H,brs), 2.47(3H,s), 3.87(2H,s), 7.50(1H,dd, J=7.8, 7.8 Hz), 7.68(1H,d J=7.8 Hz), 8.20(1H,d, J=7.8 Hz), 8.44(1H,s)

Example 43 Synthesis of N-(3-nitrophenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 42 as a starting material, the same procedure of Example 22 gave 4.1 g of the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 1.49(9H,s), 2.87(3H,s), 4.51(2H,s), 7.49-7.56(2H,m), 8.11-8.15(2H,m)

Example 44 Synthesis of N-(3-aminophenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 43 as a starting material, the same procedure of Example 2 gave 2.96 g of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.48(9H,s), 2.80(3H,s), 3.40(2H,br), 4.33(2H,s), 6.44-6.64(3H,m), 7.10(1H, dd, J=7.8, 7.8 Hz)

FAB-MS(m/z) 236(M⁺)

Example 45 Synthesis of N-(3-thioureidophenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 44 as a starting material, the same procedure of Example 3 gave 2.21 g of the titled compound (yield, 86%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 2.84(3H,s), 4.42(2H,s), 6.36(2H,brs), 7.10-7.18(3H,m), 7.39(1H, dd, J=7.8, 7.8 Hz), 8.56(1H,s)

FAB-MS(m/z) 296(M⁺+1)

Example 46 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 45 as a starting material, the same procedure of Example 27 gave 0.27 g of the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.35(3H, t, J=7.3 Hz), 1.48(9H,s), 2.81(3H,s), 3.01(2H, q, J=7.3 Hz), 4.38(2H,s), 4.55(1H,brs), 6.78-6.82 (2H,m), 6.89(1H, d, J=7.6 Hz), 7.25(1H, dd, J=7.6, 7.6 Hz)

FAB-MS(m/z) 324(M⁺+1)

Example 47 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 46 as a starting material, the same procedure of Example 5 gave 85.5 mg of the titled compound (yield, 87%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.3 Hz), 2.78(3H,s), 3.27(2H, q, J=7.3 Hz), 4.37(2H,s), 7.47-7.51(2H,m), 7.56(1H, d, J=7.6 Hz), 7.66(1H, dd, J=7.6, 7.3 Hz)

Example 48 Synthesis of N-(4-nitrophenylethyl)carbamic acid t-butyl ester

Using N-(4-nitrophenylethyl)amine hydrochloride as a starting material, the same procedure of Example 22 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 2.72-3.02(2H,m), 3.19-3.50(2H,m), 7.23(2H,d,J=9.0 Hz), 8.05(2H, d, J=9.0 Hz)

FAB-MS(m/z) 267(M⁺+1)

Example 49 Synthesis of N-(4-aminophenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 48 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 2.62-2.69(2H,m), 3.22-3.36(2H,m), 3.57(2H,brs), 4.56-4.72(1H,m), 6.61(2H, d, J=8.3 Hz), 6.95(2H, d, J=8.3 Hz)

MS(m/z) 236(M⁺)

Example 50 Synthesis of N-(4-thioureidophenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 49 as a starting material, the same procedure of Example 3 gave the titled compound (yield, 71%).

¹H-NMR(DMSO-d₆) δ: 1.39(9H,s), 2.57-2.71(2H,m), 3.10-3.21(2H,m), 6.70-6.84(1H,m), 7.13(2H, d, J=8.3 Hz), 7.30(2H, d, J=8.3 Hz), 9.59(1H,s)

MS(m/z) 295(M⁺)

Example 51 Synthesis of N-(4-(S-methylisothioureido)phenylethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 50 as a starting material, the same procedure of Example 4 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.71(3H,s), 2.99(2H,t, J=6.9 Hz), 3.26-3.38(2H,m), 4.80-4.92(1H,m), 6.75-7.08(2H,m), 7.18-7.27(4H,m)

MS(m/z) 309(M⁺)

Example 52 Synthesis of N-(4-(S-methylisothioureido)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 51 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 2.71(3H,s), 3.08(2H,t, J=7.3 Hz), 3.30-3.36(2H,m), 7.35-7.52(4H,m)

FAB-MS(m/z) 210(M⁺+1)

Example 53 Synthesis of N-(4-(N′-nitroguanidino)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 49 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 35%).

¹H-NMR(DMSO-d₆) δ: 1.38(9H,s), 2.66-2.72(2H,m), 3.10-3.18(2H,m), 6.82(1H,brs), 7.20(4H,s), 8.13(1H,brs), 9.52(1H,s)

FAB-MS(m/z) 324(M⁺+1)

Example 54 Synthesis of N-(4-(N′-nitroguanidino)phenylethyl)amine

Using the compound obtained in Example 53 as a starting material, reaction was performed as in Example 5 and the product was purified by basic silica gel column chromatography (eluent, methylene chloride:methanol=95:5) and recrystallized from a mixture of ethanol and diethyl ether to give the titled compound (yield, 57%).

¹H-NMR(DMSO-d₆) δ: 2.60-2.65(2H,m), 2.77(2H, t, J=6.9 Hz), 5.75(2H,br), 7.20(4H,s), 8.27-8.30(2H,m)

FAB-MS(m/z) 224(M⁺+1)

Example 55 Synthesis of 3-(2-bromoethyl)nitrobenzene

Carbon tetrabromide (2.48 g) and triphenylphosphine (2.35 g) were added to a mixture of 3-nitrophenethyl alcohol (1.0 g) and methylene chloride (20 ml) under cooling with ice and stirred for 30 min under cooling with ice. The reaction mixture was distilled under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 1.58 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 3.29(2H, t, J=6.9 Hz), 3.65(2H, t, J=6.9 Hz), 7.48-7.61(2H,m), 8.08-8.10(2H,m)

MS(m/z) 230(M⁺)

Example 56 Synthesis of N-(3-nitrophenylethyl)carbamic acid t-butyl ester

To a mixture of the compound (1.58 g) obtained in Example 55 and dimethyl sulfoxide (30 ml) was added 28% aqueous ammonia solution (15 ml) and the resulting mixture was stirred at room temperature for 2.5 h. The unreacted 28% aqueous ammonia solution was distilled off under reduced pressure and di-t-butyl dicarbonate (6.5 g) and triethylamine (1.3 ml) were added to the resulting residue, and reaction was performed at room temperature for 18 h. The reaction solution was diluted with ethyl acetate and washed successively with 2 N HCl and water; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 1.22 g of the titled compound (yield, 77%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.91-2.97(2H,m), 3.41-3.46(2H,m), 4.98-5.13(1H,m), 7.45-7.58(2H,m), 8.05-8.08(2H,m)

MS(m/z) 266(M⁺)

Example 57 Synthesis of N-(3-aminophenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 56 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 2.70(2H, t, J=6.9 Hz), 3.34-3.48(2H,m), 4.48-4.60(1H,m), 6.53-6.60(3H,m), 7.80(1H, t, J=7.6 Hz)

MS(m/z) 236(M⁺)

Example 58 Synthesis of N-(3-thioureidophenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 57 as a starting material, the same procedure of Example 3 gave the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.29(9H,s), 2.76-2.81(2H,m), 3.35-3.49(2H,m), 4.53-4.68(1H,m), 6.46(2H,brs), 7.02-7.35(4H,m), 8.09(1H,brs)

MS(m/z) 295(M⁺)

Example 59 Synthesis of N-(3-(S-methylisothioureido)phenylethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 58 as a starting material, the same procedure of Example 4 gave the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.39(9H,s), 2.76(3H,s), 2.81(2H, t, J=6.9 Hz), 3.35-3.38(2H,m), 4.75-4.87(1H,m), 7.15-7.19(3H,m), 7.30-7.38(1H,m), 7.72(2H,br)

MS(m/z) 309(M⁺)

Example 60 Synthesis of N-(3-(S-methylisothioureido)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 59 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 2.72(3H,s), 3.05-3.11(2H,m), 3.34(2H, t, J=7.3 Hz), 7.31-7.59(4H,m)

MS(m/z) 209(M⁺)

Example 61 Synthesis of N-(3-(N′-nitroguanidino)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 57 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 1.29(9H,s), 2,79(2H, t, J=6.3 Hz), 3.38-3.43(2H,m), 4.91-5.03(1H,m), 7.11-7.36(4H,m), 9.76(1H,brs)

FAB-MS(m/z) 324(M⁺+1)

Example 62 Synthesis of N-(3-(N′-nitroguanidino)phenylethyl)amine hydrochloride

Using the compound obtained in Example 61 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 44%).

¹H-NMR(D₂O) δ: 3.04(2H, t, J=7.3 Hz), 3.31(2H, t, J=7.3 Hz), 7.26-7.55(4H,m)

Example 63 Synthesis of 2-t-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid

A 2 N aqueous sodium hydroxide solution (12.3 ml) and di-t-butyl dicarbonate (6.36 g) were added to a mixture of 4-nitrophenylalanine (5.35 g), 1,4-dioxane (80 ml) and water (40 ml) under cooling with ice and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate and washed successively with 2 N HCl and water; the organic layer was dried with anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and n-hexane to give the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 3.06-3.25(2H,m), 4.01-4.78(1H,m), 7.45(2H, d, J=9.0 Hz), 8.08(2H, d, J=9.0 Hz)

MS(m/z) 310(M⁺)

Example 64 Synthesis of 2-t-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid methyl ester

To a mixture of the compound (1.15 g) obtained in Example 63, diethyl ether (6 ml) and methanol (14 ml), a solution of trimethylsilyldiazomethane in n-hexane (2.0 M, 7.4 ml) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure to give the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 3.08-3.31(2H,m), 3.75(3H,s), 4.38-4.78(1H,m), 4.95-5.42(1H,m), 7.28(2H, d, J=9.0 Hz), 8.09(2H, d, J=9.0 Hz)

MS(m/z) 324(M⁺)

Example 65 Synthesis of 2-t-butoxycarbonylamino-3-(4-aminophenyl)propionic acid methyl ester

Using the compound obtained in Example 64 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 2.95(2H, d, J=5.8 Hz), 3.61(2H,brs), 3.68(3H,s), 4.40-4.58(1H,m), 5.04-5.08(1H,m), 6.58(2H, d, J=8.3 Hz), 6.88(2H, d, J=8.3 Hz)

MS(m/z) 294(M⁺)

Example 66 Synthesis of 2-t-butoxycarbonylamino-3-(4-thioureidophenyl)propionic acid methyl ester

Using the compound obtained in Example 65 as a starting material, the same procedure of Example 3 gave the titled compound (yield, 73%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 2.97-3.19(2H,m), 3.74(3H,s), 4.56-4.60(1H,m), 5.11(1H, d, J=7.9 Hz), 6.28(2H,brs), 7.18(2H, d, J=5.9 Hz), 7.21(2H, d, J=5.9 Hz), 8.36(1H,s)

FAB-MS(m/z) 354(M⁺+1)

Example 67 Synthesis of 2-t-butoxycarbonylamino-3-(4-(S-methylisothioureido)phenyl)propionic acid methyl ester hydroiodide

Using the compound obtained in Example 66 as a starting material, the same procedure of Example 4 gave the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.64(3H,s), 2.99-3.17(2H,m), 3.72(3H,s), 4.48-4.53(1H,m), 5.04(1H, d, J=7.9 Hz), 6.25-6.53(2H,m), 7.13(2H, d, J=8.6 Hz), 7.17(2H, d, J=8.6 Hz)

FAB-MS(m/z) 368(M⁺⁺1)

Example 68 Synthesis of 2-amino-3-(4-(S-methylisothioureido)phenyl)propionic acid methyl ester dihydrochloride

Using the compound obtained in Example 67 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 2.70(3H,s), 3.28-3.47(2H,m), 3.85(3H,s), 4.45-4.52(1H,m), 7.39(2H, d, J=8.6 Hz), 7.45(2H, d, J=8.6 Hz)

FAB-MS(m/z) 268(M⁺+1)

Example 69 Synthesis of 2-t-butoxycarbonylamino-3-(4-(N′-nitroguanidino)phenyl)propionic acid methyl ester

Using the compound obtained in Example 65 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 3.00-3.20(2H,m), 3.73(3H,s), 4.50-4.36(1H,m), 5.20(1H,d, J=7.6 Hz), 7.20-7.28(4H,m)

FAB-MS(m/z) 382(M⁺+1)

Example 70 Synthesis of 2-amino-3-(4-(N′-nitroguanidino)phenyl)propionic acid methyl ester

Using the compound obtained in Example 69 as a starting material, the same procedure of Example 54 gave the titled compound (yield, 65%).

¹H-NMR(CDCl₃) δ: 2.80-2.91(1H,m), 3.07-3.17(1H,m), 3.74(3H,s), 3.70-3.82(1H,m), 7.24-7.34(4H,m)

FAB-MS(m/z) 282(M⁺+1)

Example 71 Synthesis of 2-t-butoxycarbonylamino-3-(4-nitrophenyl)propionic acid t-butyl ester

To a mixture of the compound (6.9 g) obtained in Example 63 and methylene chloride (70 ml) were added t-butanol (20 ml), N,N-dimethylaminopyridine (2.63 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.9 g) and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 7.64 g of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.417(9H,s), 1.419(9H,s), 3.08-3.30 (2H,m), 4.45-4.53(1H,m), 5.02-5.11(1H,m), 7.36(2H, d, J=8.6 Hz), 8.16(2H, d, J=8.6 Hz)

FAB-MS(m/z) 367(M⁺+1)

Example 72 Synthesis of 2-t-butoxycarbonylamino-3-(4-aminophenyl)propionic acid t-butyl ester

Using the compound obtained in Example 71 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 84%).

¹H-NMR(DMSO-d₆) δ: 1.36(18H,s), 2.51-2.80(2H,m), 3.88-3.94(1H,m), 4.58-4.80(2H,m), 6.48(2H, d, J=7.9 Hz), 6.86(2H, d, J=7.9 Hz)

FAB-MS(m/z) 337(M⁺+1)

Example 73 Synthesis of 2-t-butoxycarbonylamino-3-(4-thioureidophenyl)propionic acid t-butyl ester

Using the compound obtained in Example 72 as a starting material, the same procedure of Example 3 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 1.42(9H,s), 2.96-3.14(2H,m), 4.22-4.46(1H,m), 5.16(1H, d, J=7.3 Hz), 6.40(2H,brs), 7.18(2H, d, J=8.3 Hz), 7.24(2H, d, J=8.3 Hz), 8.70(1H,brs)

FAB-MS(m/z) 396(M⁺+1)

Example 74 Synthesis of 2-t-butoxycarbonylamino-3-(4-(S-methylisothioureido)phenyl)propionic acid t-butyl ester hydroiodide

Using the compound obtained in Example 73 as a starting material, the same procedure of Example 4 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.42(18H,s), 2.76(3H,s), 2.99-3.16(2H,m), 4.42-4.45(1H,m), 5.07(1H, d, J=7.9 Hz), 7.26(4H, s), 8.55(2H,br)

FAB-MS(m/z) 410(M⁺+1)

Example 75 Synthesis of 2-amino-3-(4-(S-methylisothioureido)phenyl)propionic acid dihydrochloride

Using the compound obtained in Example 74 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 91%).

¹H-NMR(D₂O) δ: 2.69(3H,s), 3.23-3.36(2H,m), 4.21-4.26(1H,m), 7.37(2H, d, J=8.6 Hz), 7.46(2H, d, J=8.6 Hz)

MS(m/z) 253(M⁺)

Example 76 Synthesis of 2-t-butoxycarbonylamino-3-(4-(N′-nitroguanidino)phenyl)propionic acid t-butyl ester

Using the compound obtained in Example 72 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 67%).

¹H-NMR(DMSO-d₆) δ: 1.36(9H,s), 1.39(9H,s), 2.80-2.98(2H,m), 4.02-4.07(1H,m), 7.10(1H, d, J=7.9 Hz), 7.19-7.26(4H,m), 8.14(1H,brs), 9.49(1H,s)

FAB-MS(m/z) 424(M⁺+1)

Example 77 Synthesis of 2-amino-3-(4-(N′-nitroguanidino)phenyl)propionic acid hydrochloride

Using the compound obtained in Example 76 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(DMSO-d₆+D₂O) δ: 3.05-3.22(2H,m), 4.12-4.17(1H,m), 7.25-7.33(4H,m)

FAB-MS(m/z) 268(M⁺+1)

Example 78 Synthesis of 2-t-butoxycarbonylamino-2-(4-aminophenyl)acetic acid methyl ester

To a mixture of 4-nitrophenylacetic acid (2.0 g), benzene (40 ml) and N-bromosuccinimide (3.3 g), 2,2′-azobis(2-methylpropionitrile)(0.16 g) was added and heated under reflux for 22 h. The reaction mixture was diluted with ethyl acetate and washed successively with 2 N HCl and water; the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate:acetic acid=75:25:1) to give 2-bromo-2-(4-nitrophenyl)acetic acid. The resulting bromo compound was mixed with 28% aqueous ammonia solution (5 ml) and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure; to the resulting residue, 1 N aqueous sodium hydroxide solution (20 ml), 1,4-dioxane (10 ml) and di-t-butyl dicarbonate (7.2 g) were added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in a mixture of methanol (20 ml) and diethyl ether (10 ml); a solution of trimethylsilyldiazomethane (2.0 M) in n-hexane was added until the reaction mixture no longer foamed; the reaction mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2-t-butoxycarbonylamino-2-(4-nitrophenyl)acetic acid methyl ester. The resulting methyl ester compound was worked up as in Example 2 to give 0.77 g of the titled compound (yield, 25%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 3.68(3H,s), 3.75(2H,brs), 5.16(1H, d, J=6.9 Hz), 5.45-5.56(1H,m), 6.60(2H, d, J=8.6 Hz), 7.10(2H, d, J=8.6 Hz)

MS(m/z) 280(M⁺)

Example 79 Synthesis of 2-t-butoxycarbonylamino-2-(4-thioureidophenyl)acetic acid methyl ester

Using the compound obtained in Example 78 as a starting material, the same procedure of Example 3 gave the titled compound (yield, 43%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 3.73(3H,s), 5.25-5.38(1H,m), 5.73-5.90(1H,m), 6.41(2H,brs), 7.23(2H, d, J=8.3 Hz), 7.42(2H, d, J=8.3 Hz), 8.70(1H,brs)

MS(m/z) 339(M⁺)

Example 80 Synthesis of 2-t-butoxycarbonylamino-2-(4-(S-methylisothioureido)phenyl)acetic acid methyl ester hydroiodide

Using the compound obtained in Example 79 as a starting material, the same procedure of Example 4 gave the titled compound (yield, 52%).

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 2.70(3H,s), 3.73(3H,s), 5.30-5.34(1H,m), 5.73-5.77(1H,m), 7.27(2H, d, J=8.3 Hz), 7.38-7.60(4H,m)

MS(m/z) 353(M⁺)

Example 81 Synthesis of 2-amino-2-(4-(S-methylisothioureido)phenyl)acetic acid methyl ester dihydrochloride

Using the compound obtained in Example 80 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 88%).

¹H-NMR(D₂O) δ: 2.71(3H,s), 3.85(3H,s), 5.40(1H,s), 7.52(2H, d, J=8.6 Hz), 7.64(2H, d, J=8.6 Hz)

MS(m/z) 253(M⁺)

Example 82 Synthesis of N-(4-aminophenylmethyl)carbamic acid t-butyl ester

Sodium hydroxide (1.77 g) was added to a mixture of N-(4-aminophenylmethyl)amine (3.0 g) and water (30 ml) under cooling with ice and stirred for 5 min under cooling with ice; thereafter, di-t-butyl dicarbonate (4.88 g) was added to the reaction mixture under cooling with ice and stirred for 10 h at room temperature. The precipitate that occurred during the reaction was collected by filtration to give 5.83 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 3.64(2H,brs), 4.18(2H, d, J=5.5 Hz), 6.64(2H, d, J=8.5 Hz), 7.07(2H, d, J=8.5 Hz)

Example 83 Synthesis of N-(4-(N′-cyclopropylguanidino)phenylmethyl)carbamic acid t-butyl ester

The compound (0.946 g) obtained in Example 82 was added to a mixture of N-cyclopropyl-S-methylisothiourea hydroiodide (1.0 g) and pyridine (10 ml) and heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 0.131 g of the titled compound (yield, 12%).

¹H-NMR(CD₃OD) δ: 0.61-0.65(2H,m), 0.76-0.86(2H,m), 1.44(9H,s), 2.72-2.86(1H,m), 4.18-4.24(2H,m), 7.23-7.34(4H,m)

Example 84 Synthesis of N-(4-(N′-cyclopropylguanidino)phenylmethyl)amine

Using the compound obtained in Example 83 as a starting material, the same procedure of Example 34 gave the titled compound (yield, 53%).

¹H-NMR(CD₃OD) δ: 0.58-0.65(2H,m), 0.73-0.86(2H,m), 2.72-2.88(1H,m), 3.76(2H,s), 7.30(2H, d, J=8.6 Hz), 7.35(2H, d, J=8.6 Hz)

Example 85 Synthesis of N-(4-(N′-nitroguanidino)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 82 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 56%).

¹H-NMR(CD₃OD) δ: 1.44(9H,s), 4.22(2H,s), 7.27(2H, d, J=8.5 Hz), 7.34(2H, d, J=8.5 Hz)

Example 86 Synthesis of N-(4-(N′-nitroguanidino)phenylmethyl)amine

Using the compound obtained in Example 85 as a starting material, the same procedure of Example 34 gave the titled compound (yield, 75%).

¹H-NMR (CD₃OD) δ: 4.12(2H,s), 7.41(2H, d, J=8.6 Hz), 7.49(2H, d, J=8.6 Hz)

Example 87 Synthesis of N-(3-(N′-cyclopropylguanidino)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 23 as a starting material, the same procedure of Example 83 gave the titled compound (yield, 8.8%).

¹H-NMR(CDCl₃) δ: 0.62-0.76(2H,m), 0.80-0.95(2H,m), 1.46(9H,s), 2.73-2.92(1H,m), 4.30(2H, d, J=5.5 Hz), 4.93-5.07(1H,m), 6.52(1H,brs), 7.12-7.39(4H,m), 7.98(1H,brs)

Example 88 Synthesis of N-(3-(N′-cyclopropylguanidino)phenylmethyl)amine

Using the compound obtained in Example 87 as a starting material, the same procedure of Example 34 gave the titled compound (yield, 51%).

¹H-NMR(CD₃OD) δ: 0.61-0.69(2H,m), 0.80-0.87(2H,m), 2.72-2.90(1H,m), 3.77(2H,s), 7.13-7.35(4H,m)

Example 89 Synthesis of N-(3-(N′-cyclopropylguanidinomethyl)phenyl)N′-nitroguanidine

Using the compound obtained in Example 34 as a starting material, the same procedure of Example 83 gave the titled compound (yield, 22%).

¹H-NMR(CD₃OD) δ: 0.57-0.62(2H,m), 0.78-0.84(2H,m), 2.52-2.68(1H,m), 4.86(2H,s), 7.18-7.40(4H,m)

Example 90 Synthesis of N-(3-(N′-nitroguanidinomethyl)phenyl)-N′-nitroguanidine

Using the compound obtained in Example 34 as a starting material and also using N-methyl-N′-nitro-N-nitrosoguanidine as a reagent, reaction was performed as in Example 83 to give the titled compound (yield, 25%).

¹H-NMR(CD₃OD) δ: 4.50(2H,s), 7.20-7.22(1H,m), 7.32-7.43(3H,m)

Example 91 Synthesis of N-(3-(S-n-propylisothioureido)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 24 as a starting material and also using n-propyl iodide as a reagent, reaction was performed as in Example 29 to give 227 mg of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.04(3H, t, J=7.3 Hz), 1.46(9H,s), 1.68-1.81(2H,m), 3.10(2H, t, J=7.3 Hz), 4.31(2H, d, J=5.6 Hz), 4.84-4.98(1H,m), 6.98-7.35(4H,m)

FAB-MS(m/z) 324(M⁺+1)

Example 92 Synthesis of N-(3-(S-n-propylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 91 as a starting material, the same procedure of Example 5 gave 173 mg of the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 1.05(3H, t, J=7.3 Hz), 1.73-1.87(2H,m), 3.22(2H, t, J=7.3 Hz), 4.25(2H,s), 7.43-7.66(4H,m)

FAB-MS(m/z) 224(M⁺+1)

Example 93 Synthesis of N-(3-(S-n-butylisothioureido)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 24 as a starting material and also using n-butyl iodide as a reagent, reaction was performed as in Example 29 to give 220 mg of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 0.94(3H, t, J=7.3 Hz), 1.39-1.53(2H,m), 1.46(9H,s), 1.64-1.75(2H,m), 3.14(2H, t, J=7.3 Hz), 4.31(2H, d, J=5.6 Hz), 4.82-4.98(1H,m), 7.02-7.36(4H,m)

FAB-MS(m/z) 338(M⁺+1)

Example 94 Synthesis of N-(3-(S-n-butylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 93 as a starting material, the same procedure of Example 5 gave 194 mg of the titled compound (yield, 96%).

¹H-NMR(D₂O) δ: 0.93(3H, t, J=7.3 Hz), 1.40-1.53(2H,m), 1.70-1.80(2H,m), 3.23(2H, t, J=7.3 Hz), 4.24(2H,s), 7.43-7.65(4H,m)

FAB-MS(m/z) 238(M⁺+1)

Example 95 Synthesis of N-(1-methyl-1-(3-(S-ethylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 3 as a starting material and also using ethyl iodide as a reagent, reaction was performed as in Example 29 to give 110 mg of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.37(9H,s), 1.37(3H, t, J=7.3 Hz), 1.60(6H,s), 3.04(2H, q, J=7.3 Hz), 4.92(1H,brs), 6.77-7.28(4H,m)

MS(m/z) 337(M⁺)

Example 96 Synthesis of N-(1-methyl-1-(3-(S-ethylisothioureido)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 95 as a starting material, the same procedure of Example 5 gave 72 mg of the titled compound (yield, 71%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 1.77(6H,s), 3.24(2H, q, J=7.3 Hz), 7.37-7.68(4H,m)

MS(m/z) 237(M⁺)

Example 97 Synthesis of N-(4-nitrophenylethyl)dimethylamine

Using the p-nitrophenethyl bromide as a starting material and also using sodium bicarbonate as a base, the same procedure of Example 37 gave 2.3 g of the titled compound (yield, 54%).

¹H-NMR(CDCl₃) δ: 2.30(6H,s), 2.56(2H, t, J=7.3 Hz), 2.89(2H, t, J=7.3 Hz), 7.37(2H, d, J=8.9 Hz), 8.14(2H, d, J=8.9 Hz),

MS(m/z) 194(M⁺)

Example 98 Synthesis of N-(4-aminophenylethyl)dimethylamine dihydrochloride

Using the compound obtained in Example 97 as a starting material and after adding a solution of hydrogen chloride (4N) in 1,4-dioxane, the same procedure of Example 2 gave 2.37 g of the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 2.27(6H,s), 2.55(2H, t, J=6.9 Hz), 2.80(2H, t, J=6.9 Hz), 7.23(2H, d, J=8.3 Hz), 7.31(2H, d, J=8.3 Hz),

MS(m/z) 164(M⁺)

Example 99 Synthesis of N-(4-(N′-nitroguanidino)phenylethyl)dimethylamine

Using the compound obtained in Example 98 as a starting material and after dissolving it in a solvent system consisting of acetonitrile and methanol, the same procedure of Example 6 gave 45 mg of the titled compound (yield, 30%).

¹H-NMR(CDCl₃) δ: 2.28(6H,s), 2.43-2.49(2H,m), 2.64-2.69(2H,m), 6.61(2H, d, J=8.2 Hz), 6.98(2H, d, J=8.2 Hz)

MS(m/z) 219(M⁺−32)

Example 100 Synthesis of N-(4-thioureidophenylethyl)dimethylamine

Using the compound obtained in Example 98 as a starting material, the same procedure of Example 3 gave 1.46 g of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 2.29(6H,s), 2.54(2H, t, J=6.9 Hz), 2.80(2H, t, J=6.9 Hz), 6.04(2H,brs), 7.15(2H, d, J=8.6 Hz), 7.28(2H, d, J=8.6 Hz), 7.85(1H,brs)

MS(m/z) 223(M⁺)

Example 101 Synthesis of N-(4-(S-methylisothioureido)phenylethyl)dimethylamine monohydrochloride mononitrate

Using the compound obtained in Example 100 as a starting material, the same procedure of Example 41 gave 0.18 g of the titled compound (yield, 99%).

¹H-NMR(DMSO-d₆) δ: 2.68(3H,s), 2.86(6H,s), 2.99-3.05(2H,m), 3.17-3.44(2H,m), 7.31(2H, d, J=8.3 Hz), 7.43(2H, d, J=8.3 Hz), 9.27(1H,brs), 9.69(1H,brs), 11.22(1H,brs)

MS(m/z) 237(M⁺)

Example 102 Synthesis of N-(4-(S-ethylthioureido)phenylethyl)dimethylamine monohydrochloride mononitrate

Using the compound obtained in Example 100 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 41 gave 107 mg of the titled compound (yield, 48%).

¹H-NMR(DMSO-d₆) δ: 1.22(3H, t, J=7.3 Hz), 2.27(6H,s), 2.50-2.60(2H,m), 2.64-2.85(2H,m), 2.89(2H, q, J=7.3 Hz), 6.74(2H, d, J=7.9 Hz), 7.07(2H, d, J=7.9 Hz)

MS(m/z) 251(M⁺)

Example 103 Synthesis of N-(4-(S-ethylisothioureido)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 50 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 29 gave the titled compound (yield, 85%).

¹H-NMR(DMSO-d₆) δ: 1.22(3H, t, J=7.3 Hz), 1.38(9H,s), 2.58-2.65(2H,m), 2.90(2H, q, J=7.3 Hz), 3.06-3.15(2H,m), 6.21-6.58(1H,brs), 6.68-6.84(2H,m), 7.05(2H, d, J=8.3 Hz)

MS(m/z) 323(M⁺)

Example 104 Synthesis of N-(4-(S-ethylisothioureido)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 103 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 93%).

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 3.02-3.10(2H,m), 3.18-3.34(4H,m), 7.36(2H, d, J=8.3 Hz), 7.47(2H, d, J=8.3 Hz)

FAB-MS(m/z) 224(M⁺+1)

Example 105 Synthesis of N-(1-(3-nitrophenyl)ethyl)methylamine

Using 3′-nitroacetophenone as a starting material, the same procedure of Example 42 gave 4.14 g of the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.38(3H, d, J=6.8 Hz), 2.32(3H,s), 3.79(1H, q, J=6.8 Hz), 7.51(1H, dd, J=7.8,7.8 Hz), 7.69-7.74(1H,m), 8.03-8.14(1H,m), 8.17-8.26(1H,m)

Example 106 Synthesis of N-(1-(3-nitrophenyl)ethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 105 as a starting material, the same procedure of Example 22 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.49(9H,s), 1.55(3H, d, J=5.8 Hz), 2.64(3H,s), 5.34-5.71(1H,m), 7.43-7.69(2H,m), 8.07-8.20(2H,m)

Example 107 Synthesis of N-(1-(3-aminophenyl)ethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 106 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 86%).

¹H-NMR (CDCl₃) δ: 1.44(3H, d, J=6.9 Hz), 1.49(9H,s), 2.58(3H,s), 3.53-3.75(2H,m), 5.37-5.59(1H,m), 6.55-6.87(3H,m), 7.11(1H, dd, J=8.2, 7.6 Hz)

Example 108 Synthesis of N-(1-(3-thioureidophenyl)ethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 107 as a starting material, the same procedure of Example 3 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.39-1.55(12H,m), 2.61(3H,s), 5.30-5.50(1H,m), 6.32(2H,brs), 7.11-7.22(3H,m), 7.38(1H, dd, J=8.2, 7.9 Hz), 8.72(1H,brs)

MS(m/z) 309(M⁺)

Example 109 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)ethyl)methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 108 as a starting material, the same procedure of Example 4 gave the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.44-1.53(12H,m), 2.61(3H,s), 2.77(3H,s), 5.26-5.57(1H,m), 7.14-7.57(4H,m), 8.51(2H,br)

Example 110 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)ethyl)methylamine dihydrochloride

Using the compound obtained in Example 109 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.71(3H, d, J=6.8 Hz), 2.63(3H,s), 2.72(3H,s), 4.45(1H, q, J=6.8 Hz), 7.34-7.84(4H,m)

MS(m/z) 223(M⁺)

Example 111 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)ethyl)methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 108 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 83%).

¹H-NMR(CDCl₃) δ: 1.40(3H, t, J=7.3 Hz), 1.43-1.61(12H,m), 2.62(3H,s),3.35(2H, q, J=7.3 Hz), 5.29-5.56(1H,m), 7.16-7.28(2H,m), 7.28-7.34(1H,m), 7.35-7.43(1H,m), 8.17(2H,br)

Example 112 Synthesis of N-(1-(3-(S-ethylisothiourido)phenyl)ethyl)methylamine dihydrochloride

Using the compound obtained in Example 111 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 98%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.3 Hz), 1.70(3H, d, J=6.8 Hz), 2.63(3H,s), 3.25(2H, q, J=7.3 Hz), 4.44(1H, q, J=6.8 Hz), 7.40-7.74(4H,m)

MS(m/z) 237(M⁺)

Example 113 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)ethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 107 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.43-1.48(12H,m), 2.56(3H,s), 3.52-3.82(1H,m), 6.52-6.68(3H,m), 7.10(1H, dd, J=8.2, 7.6 Hz)

Example 114 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)ethyl)methylamine

Using the compound obtained in Example 113 as a starting material, the same procedure of Example 55 gave the title compound (yield, 29%).

¹H-NMR(CDCl₃) δ: 1.33(3H, d, J=6.8 Hz), 2.31(3H,s), 3.54(1H, q, J=6.8 Hz), 6.49-6.73(3H,m), 7.11(1H, dd, J=7.8, 7.3 Hz)

MS(m/z) 237(M⁺)

Example 115 Synthesis of N-(3-(S-methylisothioureido)phenylmethyl)methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 45 as a starting material, the same procedure of Example 4 gave the titled compound (yield, 56%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 2.44(3H,s), 2.81(3H,s), 4.38(2H,s), 6.79-6.83(2H,m), 6.90(1H,d,J=7.6 Hz), 7.25(1H, dd, J=8.6, 7.6 Hz)

Example 116 Synthesis of N-(3-(S-methylisothioureido)phenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 115 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 56%).

¹H-NMR(D₂O) δ: 2.70(3H,s), 2.75(3H,s), 4.28(2H,s), 7.40-7.71(4H,m)

Example 117 Synthesis of N-(2-methoxy-5-nitrophenylmethyl)phthalimide

Potassium phthalimide (836 mg) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.01 g) in dimethylformamide (41 ml) and stirred at room temperature for 10 minutes. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed successively with ethyl acetate and hexane to give 1.2 g of the titled compound (yield, 94%).

¹H-NMR(DMSO-d₆) δ: 3.97(3H,s), 4.80(2H,s), 7.26(1H, d, J=9.3 Hz), 7.82-7.93(4H,m), 7.99(1H, d, J=2.9 Hz), 8.40(1H, dd, J=9.3, 2.9 Hz)

Example 118 Synthesis of N-(2-methoxy-5-nitrophenylmethyl)carbamic acid t-butyl ester

To a mixture of the compound (357 mg) obtained in Example 117 and methanol (10 ml), hydrazine monohydrate (0.06 ml) was added and stirred at room temperature for 3 h. The reaction mixture was made acidic by addition of 2 N HCl and washed with ethyl acetate. The aqueous layer was made alkaline by addition of a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in dimethylformamide (10 ml), di-t-butyl dicarbonate (274 mg) and triethylamine (0.17 ml) were added and stirred at room temperature for 3 h. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 62 mg of the titled compound (yield, 20%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 3.96(3H,s), 4.23-4.40(2H,m), 4.80-5.09(1H,m), 6.92(1H, d, J=9.3 Hz), 8.16-8.20(2H,m)

Example 119 Synthesis of N-(5-amino-2-methoxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 118 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 95%)

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 3.34(2H,br), 3.76(3H,s), 4.22(2H, d, J=5.9 Hz), 4.80-5.19(1H,m), 6.57(1H, dd, J=8.6, 3.0 Hz), 6.64-6.82(2H,m)

Example 120 Synthesis of N-(2-methoxy-5-thioureidophenylmethyl)carbamic acid t-butyl ester

To a mixture of the compound (52 mg) obtained in Example 119 and N,N-dimethylaminopyridine (53 mg) in methylene chloride (5 ml), thiophosgene (0.02 ml) was added dropwise and stirred at room temperature for 15 min. To the reaction mixture, 28% aqueous ammonia solution (5 ml) was added and stirred at room temperature for 1.5 h. After neutralization with 2 N HCl, the reaction mixture was extracted with methylene chloride and the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate) to give 58 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 3.86(3H,s), 4.27(2H, d, J=6.3 Hz), 4.90-5.05(1H,m), 5.95(2H,brs), 6.88(1H, d, J=8.6 Hz), 7.09-7.16(2H,m), 7.66(1H,brs)

Example 121 Synthesis of N-(5-(S-ethylisothioureido)-2-methoxyphenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 120 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 90%).

¹H-NMR(CDCl₃) δ: 1.38(3H, t, J=7.3 Hz), 1.45(9H,s), 3.30(2H, q, J=7.3 Hz), 3.86(3H,s), 4.18-4.31(2H,m), 5.00-5.15(1H,m), 6.89(1H, d, J=9.3 Hz), 7.14-7.26(2H,m)

MS(m/z) 339 (M⁺)

Example 122 Synthesis of N-(5-(S-ethylisothioureido)-2-methoxyphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 121 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 3.23(2H, q, J=7.3 Hz), 3.95(3H,s), 4.22(2H,s), 7.22(1H, d, J=8.9 Hz), 7.35(1H, d, J=2.6 Hz), 7.44(1H, dd, J=8.9, 2.6 Hz)

MS(m/z) 178 (M⁺−61)

Example 123 Synthesis of N-(3-nitrophenylmethyl acetamide

Acetic anhydride (0.08 ml) was added dropwise to a solution of 3-nitrobenzylamine hydrochloride (139 mg) and triethylamine (0.22 ml) in methylene chloride (10 ml) and stirred at room temperature for 2 h. To the reaction mixture, 2 N HCl was added and extraction was performed with methylene chloride; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 102 mg of the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 2.03(3H,s), 4.51(2H, d, J=5.8 Hz), 6.43-6.86(1H,m), 7.48(1H, dd, J=7.8, 6.8 Hz), 7.63(1H, d, J=7.8 Hz), 8.07-8.11(1H,m)

Example 124 Synthesis of N-(3-aminophenylmethyl)acetamide

Using the compound obtained in Example 123 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.97(3H,s), 3.70(2H,brs), 4.28(2H, d, J=5.9 Hz), 6.00-6.28(1H,m), 6.48-6.68(3H,m), 7.00-7.14(1H,m)

Example 125 Synthesis of N-(3-thioureidophenylmethyl)acetamide

Using the compound obtained in Example 124 as a starting material, the same procedure of Example 120 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.98(3H,s), 4.33(2H, d, J=5.8 Hz), 6.94(2H,brs), 7.00-7.14(1H,m), 7.20-7.37(3H,m), 7.71-7.91(1H,m), 9.49(1H,brs)

Example 126 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)acetamide hydroiodide

Using the compound obtained in Example 124 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 67%).

¹H-NMR(DMSO-d₆) δ: 1.33(3H, t, J=7.3 Hz), 1.89(3H,s), 3.31(2H, q, J=7.3 Hz), 4.30(2H, d, J=5.9 Hz), 7.19-7.22(2H,m), 7.29(1H, d, J=7.6 Hz), 7.46(1H, dd, J=7.6, 7.6 Hz), 8.30-8.50(1H,m), 9.33(2H,br)

MS(m/z) 251(M⁺)

Example 127 Synthesis of N-(2-methyl-3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

A solution of 2-methyl-3-nitrobenzyl chloride (1.07 g) in dimethylformamide (30 ml) was added dropwise to a solution of di-t-butyl iminodicarboxylate (1.38 g) and sodium hydride (content, 60%; 0.30 g) in dimethylformamide (30 ml) at 0° C. Following 1-h stirring at room temperature, the temperature of the mixture was raised to 80° C. and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=10:1) to give 1.49 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 1.48(9H,s), 2.43(3H,s), 4.37-4.41(2H,m), 7.30(1H, dd, J=8.1, 8.0 Hz), 7.51(1H, d, J=8.0 Hz), 7.69(1H, d, J=8.1 Hz)

Example 128 Synthesis of N-(3-amino-2-methylphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 127 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ1.46(9H,s), 2.11(3H,s), 3.62(2H,brs), 4.29(2H, d, J=5.3 Hz), 4.55-4.78(1H,m), 6.63-6.71(2H,m), 6.99(1H, dd, J=7.9, 7.6 Hz)

MS(m/z) 236(M⁺)

Example 129 Synthesis of N-(2-methyl-3-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 128 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 2.27(3H,s), 4.34(2H, d, J=5.6 Hz), 4.71-4.94(1H,m), 5.83(2H,br), 7.15-7.30(5H,m), 7.71(1H,brs)

Example 130 Synthesis of N-(3-(S-ethylisothioureido)-2-methylphenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 129 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.40(3H, t, J=7.8 Hz), 1.47(9H,s), 2.32(3H,s), 3.27(2H, q, J=7.8 Hz), 4.36(2H, d, J=5.7 Hz), 4.66-4.86(1H,m), 7.19-7.37(3H,m)

Example 131 Synthesis of N-(3-(S-ethylisothioureido)-2-methylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 130 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 66%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.6 Hz), 2.29(3H,s), 3.25(2H, q, J=7.6 Hz), 4.31(2H,s), 7.37-7.54(3H,m)

MS(m/z) 223(M⁺)

Example 132 Synthesis of (2-chloro-3-nitrophenyl)methanol

A borane-tetrahydrofuran complex (1.0 M, 20 ml) was added dropwise to a solution of 2-chloro-3-nitrobenzoic acid (5.0 g) in anhydrous tetrahydrofuran (30 ml) in a nitrogen atmosphere and the mixture was heated under reflux for 16 h. Water was added to the reaction mixture which was extracted with ethyl acetate; the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous-sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:2) to give 3.5 g of the titled compound (yield, 84%).

¹H-NMR(CDCl₃) δ: 2.04(1H, t, J=5.9 Hz), 4.88(2H, d, J=5.9 Hz), 7.45(1H, dd, J=7.9, 7.9 Hz), 7.72-7.82(2H,m)

Example 133 Synthesis of N-(2-chloro-3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

A mixture of the compound (1.01 g) obtained in Example 132 and thionyl chloride (50 ml) was heated under reflux for 48 h. The reaction mixture was concentrated under reduced pressure; the resulting residue was dissolved in dimethylformamide (25 ml) and added dropwise to a solution of sodium hydride (content, 60%; 0.24 g) and di-t-butyl iminodicarboxylate (1.29 g) in dimethylformamide (25 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h and stirred at 80° C. for 2 h. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:1) to give 1.70 g of the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 1.48(9H,s), 4.97(2H,s), 7.32-7.42(2H,m), 7.66-7.72(1H,m)

Example 134 Synthesis of N-(3-amino-2-chlorophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 133 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 67%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 1.48(9H,s), 4.10(2H,brs), 4.86(2H,s), 6.53-6.66(2H,m), 7.06(1H, dd, J=8.3, 7.8 Hz)

MS(m/z) 356(M⁺)

Example 135 Synthesis of N-(2-chloro-3-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 134 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 1.47(9H,s), 4.90(2H,s), 6.35(2H,brs), 7.11-7.13(1H,m), 7.31-7.43(2H,m), 8.05(1H,brs)

Example 136 Synthesis of N-(2-chloro-3-(S-ethylisothioureido)phenylmethy)iminodicarboxylic acid di-t-butyl ester hydroiodide

Using the compound obtained in Example 135 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 38%).

¹H-NMR(CDCl₃) δ: 1.40(3H, t, J=7.3 Hz), 1.45(18H,s), 3.34(2H, q, J=7.3 Hz), 4.92(2H,s), 7.22-7.36(3H,m)

Example 137 Synthesis of N-(2-chloro-3-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 136 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 97%).

¹H-NMR(D₂O) δ: 1.44(3H, t, J=7.3 Hz), 3.26(2H, q, J=7.3 Hz), 4.42(2H,s), 7.53-7.70(3H,m)

MS(m/z) 243(M⁺)

Example 138 Synthesis of N-(1-(3-nitrophenyl)cyclohexyl)carbamic acid t-butyl ester Example 138a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,5-diboromopentane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclohexanecarboxylic acid.

¹H-NMR(CDCl₃) δ: 1.19-1.86(8H,m), 2.49-2.54(2H,m), 7.49-7.81(2H,m), 8.10-8.33(2H,m)

Example 138b

Using 1-(3-nitrophenyl)cyclohexanecarboxylic acid as a starting material, the same procedure of Example 1c gave 110 mg of the titled compound (yield, 28%).

¹H-NMR(CDCl₃) δ: 1.39(9H,s), 1.52-1.82(8H,m), 2.21-2.25(2H,m), 4.94(1H,brs), 7.46-7.77(2H,m), 8.06-8.29(2H,m)

Example 139 Synthesis of N-(1-(3-aminophenyl)cyclohexyl)carbamic acid t-butyl ester

Using the compound obtained in Example 138 as a starting material, the same procedure of Example 2 gave 877 mg of the titled compound (yield, 65%).

¹H-NMR(CDCl₃) δ: 1.38(9H,s), 1.48-1.78(8H,m), 2.08-2.30(2H,m), 3.59(2H,brs), 4.75(1H,brs), 6.52-6.82(3H,m), 7.06-7.12(1H,m)

Example 140 Synthesis of N-(1-(3-thioureidophenyl)cyclohexyl)carbamic acid t-butyl ester

Using the compound obtained in Example 139 as a starting material, the same procedure of Example 120 gave 224 mg of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.50-1.81(8H,m), 2.06-2.17(2H,m), 4.93(1H,brs), 6.21(2H,brs), 7.03-7.42(4H,m), 8.03(1H,brs)

Example 141 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)cyclohexyl)carbamic acid t-butyl ester

Using the compound obtained in Example 140 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 85 mg of the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 1.49-1.83(8H,m), 2.15-2.20(2H,m), 2.46(3H,s), 4.55(1H,brs), 4.81(1H,brs), 6.75-7.26(4H,m)

Example 142 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)cyclohexyl)amine dihydrochloride

Using the compound obtained in Example 141 as a starting material, the same procedure of Example 5 gave 74 mg of the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 1.43-2.02(8H,m), 2.48-2.52(2H,m), 2.69(3H,s), 7.44-7.78(4H,m)

FAB-MS(m/z) 264(M⁺+1)

Example 143 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclohexyl)carbamic acid t-butyl ester

Using the compound obtained in Example 140 as a starting material, the same procedure of Example 95 gave 108 mg of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.34-1.39(3H,m), 1.37(9H,s), 1.49-1.82(8H,m), 2.15-2.20(2H,m), 2.92-3.20(2H,m), 4.52(1H,brs), 4.80(1H,brs), 6.75-7.28(4H,m)

Example 144 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclohexyl)amine dihydrochloride

Using the compound obtained in Example 143 as a starting material, the same procedure of Example 5 gave 79 mg of the titled compound (yield, 87%).

¹H-NMR(D₂O) δ: 1.32-2.08(8H,m), 1.41(3H, t, J=7.3 Hz), 2.47-2.52(2H,m), 3.23(2H, q, J=7.3 Hz), 7.43-7.74(4H,m)

FAB-MS(m/z) 278(M⁺+1)

Example 145 Synthesis of N-(1-(3-(S-n-propylisothioureido)phenyl)cyclohexyl)carbamic acid t-butyl ester

Using the compound obtained in Example 140 as a starting material, the same procedure of Example 91 gave 78 mg of the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.02(3H, t, J=7.3 Hz), 1.36(9H,s), 1.49-1.82(10H,m), 2.15-2.20(2H,m), 2.90-3.14(2H,m), 4.52(1H,brs), 4.80(1H,brs), 6.73-7.28(4H,m)

Example 146 Synthesis of N-(1-(3-(S-n-propylisothioureido)phenyl)cyclohexyl)amine dihydrochloride

Using the compound obtained in Example 145 as a starting material, the same procedure of Example 5 gave 64 mg of the titled compound (yield, 98%).

¹H-NMR(D₂O) δ: 1.04(3H, t, J=7.3 Hz), 1.39-2.05(10H,m), 2.47-2.52 (2H,m), 3.20(2H, t, J=7.3 Hz), 7.43-7.74(4H,m)

FAB-MS(m/z) 292(M⁺+1)

Example 147 Synthesis of N-(1-(3-nitrophenyl)cyclopentyl)carbamic acid t-butyl ester Example 147a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,4-dibromobutane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclopentanecarboxylic acid.

¹H-NMR(CDCl₃) δ: 78-2.05(6H,m), 2.68-2.74(2H,m), 7.46-7.74(2H,m), 8.10-8.25(2H,m)

Example 147b

Using the 1-(3-nitrophenyl)cyclopentanecarboxylic acid as a starting material, the same procedure of Example 1c gave 211 mg of the titled compound (yield, 54%).

¹H-NMR(CDCl₃) δ: 1.37(9H,s), 1.86-2.23(8H,m), 4.97(1H,brs), 7.45-7.78(2H,m), 8.06-8.27(2H,m)

Example 148 Synthesis of N-(1-(3-aminophenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 147 as a starting material, the same procedure of Example 2 gave 1.81 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.72-2.18(8H,m), 3.60(2H,brs), 4.83(1H,brs), 6.51-7.11(4H,m)

Example 149 Synthesis of N-(1-(3-thioureidophenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 148 as a starting material, the same procedure of Example 120 gave 296 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.33(9H,s), 1.84-2.21(8H,m), 4.91(1H,brs), 6.24 (2H,brs), 6.87-7.40(4H,m), 7.90(1H,brs)

Example 150 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 149 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 82 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.34(9H,s), 1.80-2.18(8H,m), 2.47(3H,s), 4.57(1H,brs), 4.84(1H,brs), 6.78-7.27(4H,m)

Example 151 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)cyclopentyl)amine dihydrochloride

Using the compound obtained in Example 150 as a starting material, the same procedure of Example 5 gave 72 mg of the titled compound (yield, 95%).

¹H-NMR(D₂O) δ: 1.87-1.97(4H,m), 2.30-2.35(4H,m), 2.70(3H,s), 7.39-7.67(4H,m)

FAB-MS(m/z) 250(M⁺+1)

Example 152 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 149 as a starting material, the same procedure of Example 95 gave 97 mg of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.26-1.39(12H,m), 1.80-2.30(8H,m), 2.95-3.20(2H,m), 4.55(1H,brs), 4.86(1H,brs), 6.77-7.24(4H,m)

Example 153 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclopentyl)amine dihydrochloride

Using the compound obtained in Example 152 as a starting material, the same procedure of Example 5 gave 79 mg of the titled compound (yield, 88%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 1.88-1.98(4H,m), 2.30-2.35(4H,m), 3.24(2H, q, J=7.3 Hz), 7.39-7.68(4H,m)

FAB-MS(m/z) 264(M⁺+1)

Example 154 Synthesis of N-(1-(3-(S-n-propylisothioureido)phenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 149 as a starting material, the same procedure of Example 91 gave 94 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.03(3H, t, J=7.3 Hz), 1.34(9H,s), 1.70-2.17(10H,m), 2.95-3.15(2H,m), 4.54(1H,brs), 4.85(1H,brs), 6.76-7.25(4H,m)

Example 155 Synthesis of N-(1-(3-(S-n-propylisothioureido)phenyl)cyclopentyl)amine dihydrochloride

Using the compound obtained in Example 154 as a starting material, the same procedure of Example 5 gave 83 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.04(3H, t, J=7.3 Hz), 1.73-1.97(6H,m), 2.29-2.35(4H,m), 3.20(2H, t, J=7.3 Hz), 7.40-7.64(4H,m)

FAB-MS(m/z) 278(M⁺+1)

Example 156 Synthesis of N-(1-(3-nitrophenyl)cyclobutyl)carbamic acid t-butyl ester Example 156a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,3-dibromopropane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclobutanecarboxylic acid.

¹H-NMR(CDCl₃) δ: 1.86-2.27(2H,m), 2.50-2.62(2H,m), 2.88-2.97(2H,m), 7.48-7.64(2H,m), 8.10-8.17(2H,m)

Example 156b

Using the 1-(3-nitrophenyl)cyclobutanecarboxylic acid as a starting material, the same procedure of Example 1c gave 2.0 g of the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 1.85-2.26(2H,m), 2.46-2.62(4H,m), 5.28(1H,brs), 7.51-8.28(4H,m)

Example 157 Synthesis of N-(1-(3-aminophenyl)cyclobutyl)carbamic acid t-butyl ester

Using the compound obtained in Example 156 as a starting material, the same procedure of Example 2 gave 1.2 g of the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 1.72-2.12(2H,m), 2.48-2.53(4H,m), 3.64(2H,brs), 4.99(1H,brs), 6.54-7.15(4H,m)

Example 158 Synthesis of N-(1-(3-thioureidophenyl)cyclobutyl)carbamic acid t-butyl ester

Using the compound obtained in Example 157 as a starting material, the same procedure of Example 120 gave 302 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.34(9H,s), 1.80-2.24(2H,m), 2.37-2.59(4H,m), 5.24(1H,brs), 6.34(2H,brs), 7.04-7.45(4H,m), 8.24(1H,s)

Example 159 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)cyclobutyl)carbamic acid t-butyl ester

Using the compound obtained in Example 158 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 150 mg of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.76-2.20(2H,m), 2.46-2.72(7H,m), 4.56 (1H,brs), 5.07(1H,brs), 6.78-7.25(4H,m)

Example 160 Synthesis of N-(1-(3-(S-methylisothioureido)phenyl)cyclobutyl)amine dihydrochloride

Using the compound obtained in Example 159 as a starting material, the same procedure of Example 5 gave 110 mg of the titled compound (yield, 86%).

¹H-NMR(D₂O) δ: 1.88-2.29(2H,m), 2.60-2.84(7H,m), 7.42-7.69(4H,m)

Example 161 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclobutyl)carbamic acid t-butyl ester

Using the compound obtained in Example 158 as a starting material, the same procedure of Example 95 gave 150 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.26-1.43(12H,m), 1.79-2.16(2H,m), 2.48-2.54(4H,m), 2.90-3.14(2H,m), 4.54(1H,brs), 5.07(1H,brs), 6.78-7.24(4H,m)

Example 162 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclobutyl)amine dihydrochloride

Using the compound obtained in Example 161 as a starting material, the same procedure of Example 5 gave 100 mg of the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 1.94-2.23(2H,m), 2.60-2.84(4H,m), 3.24(2H, q, J=7.3 Hz), 7.42-7.69(4H,m)

Example 163 Synthesis of N-(1-(3-nitrophenyl)cyclopropyl)carbamic acid t-butyl ester Example 163a

Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,2-dibromoethane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclopropanecarboxylic acid.

¹H-NMR(CDCl₃) δ: 1.34(2H, dd, J=7.3, 4.3 Hz), 3.56(2H, dd, J=7.3, 4.3 Hz), 7.46-7.71(2H,m), 8.13-8.21(2H,m)

Example 163b

Using the 1-(3-nitrohenyl)cyclopropanecarboxylic acid as a starting material, the same procedure of Example 1c gave 162 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.31-1.45(13H,m), 5.34(1H,brs), 7.43-7.48(2H,m), 8.03-8.08(2H,m)

Example 164 Synthesis of N-(1-(3-aminophenyl)cyclopropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 163 as a starting material, the same procedure of Example 2 gave 18.7 mg of the titled compound (yield, 2%).

¹H-NMR(CDCl₃) δ: 1.18-1.28(4H,m), 1.43(9H,s), 3.61(2H,brs), 5.24 (1H,brs), 6.49-6.61(2H,m), 7.03-7.09(2H,m)

Example 165 Synthesis of N-(1-(3-thioureidophenyl)cyclopropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 164 as a starting material, the same procedure of Example 120 gave 20 mg of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.24-1.35(4H,m), 1.43(9H,s), 5.31(1H,brs), 6.21 (2H,brs), 7.03-7.37(4H,m), 8.10(1H,brs)

Example 166 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclopropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 165 as a starting material, the same procedure of Example 95 gave 20 mg of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.21-1.25(4H,m), 1.35(3H, t, J=7.3 Hz), 1.43(9H,s), 2.95-3.10(2H,m), 5.29(1H,brs), 6.73-6.88(2H,m), 7.18-7.27(2H,m)

Example 167 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)cyclopropyl)amine dihydrochloride

Using the compound obtained in Example 166 as a starting material, the same procedure of Example 5 gave 21 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.31-1.49(7H,m), 3.23(2H, q, J=7.3 Hz), 7.39-7.44(2H,m), 7.59-7.61(2H,m)

Example 168 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)cyclohexyl)carbamic acid t-butyl ester

Using the compound obtained in Example 139 as a starting material, the same procedure of Example 6 gave 63 mg of the titled compound (yield, 32%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.51-1.86(8H,m), 2.14-2.19(2H,m), 4.95(1H,brs), 7.15-7.47(4H,m), 9.66(1H,brs)

Example 169 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)cyclohexyl)amine hydrochloride

Using the compound obtained in Example 168 as a starting material, the same procedure of Example 5 gave 51 mg of the titled compound (yield, 97%).

¹H-NMR(D₂O) δ: 1.43-2.07(8H,m), 2.48-2.53(2H,m), 7.37-7.62(4H,m)

Example 170 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 148 as a starting material, the same procedure of Example 6 gave 121 mg of the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.34(9H,s), 1.87-2.24(8H,m), 4.94(1H,brs), 7.14-7.45(4H,m), 9.67(1H,brs)

Example 171 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)cyclopentyl)amine hydrochloride

Using the compound obtained in Example 170 as a starting material, the same procedure of Example 5 gave 78 mg of the titled compound (yield, 98%).

¹H-NMR(D₂O) δ: 1.90-1.97(4H,m), 2.29-2.32(4H,m), 7.37-7.61(4H,m)

Example 172 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)cyclobutyl)carbamic acid t-butyl ester

Using the compound obtained in Example 157 as a starting material, the same procedure of Example 6 gave 106 mg of the titled compound (yield, 53%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.87-2.28(2H,m), 2.38-2.63(4H,m), 5.26(1H,brs), 7.15-7.48(4H,m), 9.69(1H,brs)

Example 173 Synthesis of N-(1-(3-(N′-nitroguanidino)phenyl)cyclobutyl)amine hydrochoride

Using the compound obtained in Example 172 as a starting material, the same procedure of Example 5 gave 72 mg of the titled compound (yield, 98%).

¹H-NMR(D₂O) δ: 1.90-2.28(2H,m), 2.59-2.84(4H,m), 7.38-7.63(4H,m)

Example 174 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 10 as a starting material, the same procedure of Example 95 gave 71 mg of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.34-1.44(15H,m), 2.90-3.12(2H,m), 4.42-4.54(1H,m), 4.76(1H,brs), 6.82-7.29(4H,m)

Example 175 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 174 as a starting material, the same procedure of Example 5 gave 53 mg of the titled compound (yield, 97%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.6 Hz), 1.67(3H, d, J=6.9 Hz), 3.25 (2H, q, J=7.6 Hz), 4.60(1H, q, J=6.9 Hz), 7.42-7.67(4H,m)

Example 176 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 17 as a starting material, the same procedure of Example 95 gave 820 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 0.88(3H, t, J=7.3 Hz), 1.30-1.50(12H,m), 1.72-1.78(2H,m), 3.00-3.17(2H,m), 4.40-4.58(2H,m), 4.78 (1H,brs), 6.80-6.94(2H,m), 7.22-7.28(2H,m)

Example 177 Synthesis of N-(1-(3-(S-ethylisothioureido)phenyl)propyl)amine dihydrochloride

Using the compound obtained in Example 176 as a starting material, the same procedure of Example 5 gave 653 mg of the titled compound (yield, 82%).

¹H-NMR(D₂O) δ: 0.89(3H, t, J=7.3 Hz), 1.42(3H, t, J=7.3 Hz), 1.94-2.13(2H,m), 3.24(2H, q, J=7.3 Hz), 4.33(1H, t, J=7.3 Hz), 7.44-7.68(4H,m)

Example 178 Synthesis of 2-methyl-2-(4-nitrophenyl)propanol Example 178a

Using 4-nitrophenylacetic acid diphenylmethyl ester as a starting material and also using methyl iodide (2 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-methyl-2-(4-nitrophenyl)propionic acid.

¹H-NMR(CDCl₃) δ: 1.65(6H,s), 7.57(2H, d, J=8.9 Hz), 8.20(2H, d, J=8.9 Hz)

Example 178b

Using the 2-methyl-2-(4-nitrophenyl)propionic acid as a starting material, the same procedure of Examaple 132 gave 172 mg of the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 1.38(6H,s), 3.69(2H,s), 7.56(2H, d, J=8.9 Hz), 8.18(2H, d, J=8.9 Hz)

Example 179 Synthesis of N-(2-methyl-2-(4-nitrophenyl)propyl)phthalimide

A solution of the compound (152 mg) obtained in Example 178 in anhydrous tetrahydrofuran (10 ml) was added drowise to a mixture of triphenylphosphine (484 mg), diethyl azodicarboxylate (0.29 ml) and anhydrous tetrahydrofuran (20 ml) at 0° C. in a nitrogen atmosphere. Then, a solution of phthalimide (272 mg) in anhydrous tetrahydrofuran (10 ml) was added dropwise to the reaction mixture at 0° C., stirred for 10 min and stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane ethyl acetate=8:2) to give 439 mg of the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 1.46(6H,s), 3.84(2H,s), 7.72(2H, d, J=8.9 Hz), 7.75-7.83(4H,m), 8.17(2H, d, J=8.9 Hz)

Example 180 Synthesis of N-(2-methyl-2-(4-nitrophenyl)propyl)amine

To a mixture of the compound (152 mg) obtained in Example 179, methanol (10 ml) and chloroform (10 ml), hydrazine monohydrate (0.05 ml) was added and heated under reflux for 24 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; following addition of 2 N HCl, the mixture was washed with ethyl acetate. Then, the aqueous layer was made alkaline with a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 71 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.36(6H,s), 2.87(2H,s), 7.52(2H, d, J=8.9 Hz), 8.18(2H, d, J=8.9 Hz)

Example 181 Synthesis of N-(2-methyl-2-(4-nitrophenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 180 as a starting material, the same procedure of Example 22 gave 77 mg of the titled compound (yield, 86%).

¹H-NMR(CDCl₃) δ: 1.37(6H,s), 1.38(9H,s), 3.36(2H, d, J=6.3 Hz), 4.30-4.40(1H,m), 7.53(2H, d, J=8.9 Hz), 8.18(2H, d, J=8.9 Hz)

Example 182 Synthesis of N-(2-(4-aminophenyl)-2-methylpropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 181 as a starting material, the same procedure of Example 2 gave 796 mg of the titled compound (yield, 65%).

¹H-NMR(CDCl₃) δ: 1.26(6H,s), 1.40(9H,s), 3.26(2H, d, J=5.9 Hz), 3.60(2H,brs), 4.20-4.38(1H,m), 6.66(2H, d, J=8.6 Hz), 7.12(2H, d, J=8.6 Hz)

Example 183 Synthesis of N-(2-methyl-2-(4-thioureidophenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 182 as a starting material, the same procedure of Example 120 gave 240 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.32(6H,s), 1.38(9H,s), 3.30(2H, d, J=6.3 Hz), 4.38-4.50(1H,m), 6.20(2H,brs), 7.20(2H, d, J=8.3 Hz), 7.42(2H, d, J=8.3 Hz), 8.19(1H,brs)

Example 184 Synthesis of N-(2-(4-(S-ethylisothioureido)phenyl)-2-methylpropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 183 as a starting material, the same procedure of Example 95 gave 120 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.30(6H,s), 1.34-1.40(12H,m), 3.00-3.18(2H,m), 3.29(2H, d, J=6.3 Hz), 4.20(1H,brs), 4.40-4.60(1H,m), 6.80-6.95(2H,m), 7.28(2H, d, J=7.6 Hz)

Example 185 Synthesis of N-(2-(4-(S-ethylisothioureido)phenyl)-2-methylpropyl)amine dihydrochloride

Using the compound obtained in Example 184 as a starting material, the same procedure of Example 5 gave 110 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.39-1.46(9H,m), 3.19-3.29(4H,m), 7.40(2H, d, J=8.6 Hz), 7.63(2H, d, J=8.6 Hz)

Example 186 Synthesis of N-(2-methyl-2-(4-(N′-nitroguanidino)phenyl)propyl)carbamic acid t-butyl ester

Using the compound obtained in Example 182 as a starting material, the same procedure of Example 6 gave 163 mg of the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.34(6H,s), 1.39(9H,s), 3.32(2H, d, J=6.3 Hz), 4.18-4.28(1H,m), 7.29(2H, d, J=8.3 Hz), 7.48(2H, d, J=8.3 Hz), 9.85(1H,brs)

Example 187 Synthesis of N-(2-methyl-2-(4-(N′-nitroguanidino)phenyl)propyl)amine hydrochloride

Using the compound obtained in Example 186 as a starting material, the same procedure of Example 5 gave 90 mg of the titled compound (yield, 92%).

¹H-NMR(D₂O) δ: 1.45(6H,s), 3.27(2H,s), 7.38(2H, d, J=8.6 Hz), 7.58(2H, d, J=8.6 Hz)

Example 188 Synthesis of N-(1,1-dimethyl-2-(4-nitrophenyl)ethyl)amine

A solution of phentermine (1.0 g) in chloroform (20 ml) was added dropwise to sulfuric acid (3.57 ml) at 0° C.; then fuming nitric acid (specific gravity=1.52; 2.8 ml) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h, made alkaline with water and a 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 367 mg of the titled compound (yield, 28%).

¹H-NMR(CDCl₃) δ: 1.15(6H,s), 2.78(2H,s), 7.37(2H, d, J=8.6 Hz), 8.16(2H, d, J=8.6 Hz)

Example 189 Synthesis of N-(1,1-dimethyl-2-(4-nitrophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 188 as a starting material, the same procedure of Example 22 gave 473 mg of the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.28(6H,s), 1.48(9H,s), 3.15(2H,s), 4.24(1H,brs), 7.31(2H, d, J=8.6 Hz), 8.07(2H, d, J=8.6 Hz)

Example 190 Synthesis of N-(2-(4-aminophenyl)-1,1-dimethylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 189 as a starting material, the same procedure of Example 2 gave 350 mg of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.24(6H,s), 1.46(9H,s), 2.84(2H,s), 3.58(2H,brs), 4.27(1H,brs), 6.61(2H, d, J=8.2 Hz), 6.94(2H, d, J=8.2 Hz)

Example 191 Synthesis of N-(1,1-dimethyl-2-(4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 190 as a starting material, the same procedure of Example 120 gave 152 mg of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.26(6H,s), 1.47(9H,s), 3.02(2H,s), 4.26(1H,brs), 6.06(2H,brs), 7.14(2H, d, J=8.3 Hz), 7.23(2H, d, J=8.3 Hz), 7.85(1H,brs)

Example 192 Synthesis of N-(1,1-dimethyl-2-(4-(S-ethylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 191 as a starting material, the same procedure of Example 95 gave 150 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.25(6H,s), 1.37(3H, t, J=7.3 Hz), 1.46(9H,s), 2.92(2H,s), 2.98-3.18(2H,m), 4.25(1H,brs), 4.49(1H,brs), 6.78-6.90(2H,m), 7.09(2H, d, J=7.9 Hz)

Example 193 Synthesis of N-(1,1-dimethyl-2-(4-(S-ethylisothioureido)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 192 as a starting material, the same procedure of Example 5 gave 140 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.37(6H,s), 1.41(3H, t, J=7.6 Hz), 3.02(2H,s), 3.23(2H, q, J=7.6 Hz), 7.37(2H, d, J=8.3 Hz), 7.44(2H, d, J=8.3 Hz)

Example 194 Synthesis of N-(1,1-dimethyl-2-(4-(N′-nitroguanidino)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 190 as a starting material, the same procedure of Example 6 gave 70 mg of the titled compound (yield, 43%).

¹H-NMR(CDCl₃) δ: 1.28(6H,s), 1.48(9H,s), 3.05(2H,s), 4.30(1H,brs), 7.23(2H, d, J=8.6 Hz), 7.28(2H, d, J=8.6 Hz), 9.73(1H,brs)

Example 195 Synthesis of N-(1,1-dimethyl-2-(4-(N′-nitroguanidino)phenyl)ethyl)amine hydrochloride

Using the compound obtained in Example 194 as a starting material, the same procedure of Example 5 gave 56 mg of the titled compound (yield, 97%).

¹H-NMR(D₂O) δ: 1.37(6H,s), 3.00(2H,s), 7.34-7.44(4H,m)

Example 196 Synthesis of (4-methoxy-3-nitrophenyl)methanol

Using 4-methoxy-3-nitrobenzoic acid as a starting material, the same procedure of Example 132 gave 5.4 g of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.87(1H, t, J=5.9 Hz), 3.96(3H,s), 4.69(2H, d, J=5.9 Hz), 7.08(1H, d, J=8.6 Hz), 7.55(1H, dd, J=8.6, 2.3 Hz), 7.85(1H, d, J=2.3 Hz)

Example 197 Synthesis of N-(4-methoxy-3-nitrophenylmethyl)phthalimide

Using the compound obtained in Example 196 as a starting material, the same procedure of Example 179 gave 2.74 g of the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 3.93(3H,s), 4.82(2H,s), 7.03(1H, d, J=8.8 Hz), 7.65(1H, dd, J=8.8, 2.4 Hz), 7.70-7.75(2H,m), 7.84-7.89(2H,m), 7.92(1H,d, J=2.4 Hz)

Example 198 Synthesis of N-(4-methoxy-3-nitrophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 197 as a starting material, reaction was performed as in Example 118 to give 1.47 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 3.95(3H,s) 4.29(2H, d, J=5.4 Hz), 4.93(1H,br), 7.05(1H, d, J=8.8 Hz), 7.49(1H, dd, J=8.8, 2.4 Hz), 7.77(1H, d, J=2.4 Hz)

Example 199 Synthesis of N-(3-amino-4-methoxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 198 as a starting material, the same procedure of Example 2 gave 1.24 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 3.79(2H,br), 3.83(3H,s), 4.16(2H, d, J=5.6 Hz), 4.71(1H,br), 6.60-6.65(2H,m), 6.72(1H, d, J=8.3 Hz)

Example 200 Synthesis of N-(4-methoxy-3-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 199 as a starting material, reaction was performed as in Example 120 to give 605 mg of the titled compound (yield, 97%).

¹H-NMR(DMSO-d₆) δ: 1.39(9H,s), 3.79(3H,s), 4.03(1H, d, J=5.9 Hz), 6.92-7.03(2H,m), 7.23-7.27(1H,m), 7.30(2H,br), 7.61(1H,s), 8.96(1H,s)

Example 201 Synthesis of N-(3-(S-ethylisothioureido)-4-methoxyphenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 200 as a starting material, the same procedure of Example 27 gave 591 mg of the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.39(3H, t, J=7.3 Hz), 1.46(9H,s), 3.30(2H, q, J=7.3 Hz), 3.86(3H,s), 4.25(2H, d, J=5.6 Hz), 4.93(1H,br), 6.93(1H, d, J=8.4 Hz), 7.22-7.30(3H,m)

Example 202 Synthesis of N-(3-(S-ethylisothioureido)-4-methoxyphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 201 as a starting material, the same procedure of Example 5 gave 102 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.33(3H, t, J=7.3 Hz), 3.29(2H, q, J=7.3 Hz), 3.86(3H,s), 3.97-4.01(2H,m), 7.24(1H, d, J=8.6 Hz), 7.44(1H, d, J=2.0 Hz), 7.56(1H, dd, J=8.6, 2.0 Hz), 8.45(3H,br), 9.53(1H,br), 11.28(1H,br)

Example 203 Synthesis of (4-chloro-3-nitrophenyl)methanol

Using 4-chloro-3-nitrobenzoic acid as a starting material, the same procedure of Example 132 gave 1.53 g of the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.96(1H, t, J=5.4 Hz), 4.78(2H, d, J=5.4 Hz), 7.48-7.57(2H,m), 7.90(1H,s)

Example 204 Synthesis of N-(4-chloro-3-nitrophenylmethyl)phthalimide

Using the compound obtained in Example 203 as a starting material, the same procedure of Example 179 gave 1.65 g of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 4.87(2H,s), 7.50(1H, d, J=8.3 Hz), 7.60(1H, dd, J=8.3, 2.0 Hz), 7.73-7.80(2H,m), 7.83-7.91(2H,m), 7.93(1H, d, J=2.0 Hz)

Example 205 Synthesis of N-(4-chloro-3-nitrophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 204 as a starting material, the same procedure of Example 118 gave 626 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 4.33-4.37(2H,m), 5.01(1H,br), 7.41-7.54(2H,m), 7.79(1H, d, J=1.5 Hz)

Example 206 Synthesis of N-(3-amino-4-chlorophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 205 as a starting material, the same procedure of Example 2 gave 376 mg of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 4.18-4.22(2H,m), 4.79(1H,br), 6.59(1H, dd, J=8.3, 1.5 Hz), 6.69(1H, d, J=1.5 Hz), 7.17(1H, d, J=8.3 Hz)

Example 207 Synthesis of N-(4-chloro-3-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 206 as a starting material, the same procedure of Example 120 gave 100 mg of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 4.28(2H, d, J=5.9 Hz), 5.26(1H,br), 6.49 (2H,br), 7.14(1H, dd, J=8.3, 1.5 Hz), 7.37-7.42(2H,m), 8.15(1H,br)

Example 208 Synthesis of N-(4-chloro-3-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 207 as a starting material, the same procedure of Example 27 gave 113 mg of the titled compound (yield, 75%).

¹H-NMR(CDCl₃) δ: 1.40(3H, t, J=7.3 Hz), 1.46(9H,s), 3.20(2H, q, J=7.3 Hz), 4.28(2H, d, J=6.3 Hz), 4.94(1H,br), 7.10-7.14(2H,m), 7.40(1H, d, J=9.3 Hz)

Example 209 Synthesis of N-(4-chloro-3-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 208 as a starting material, the same procedure of Example 5 gave 97 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.34(3H, t, J=7.3 Hz), 3.32(2H, q, J=7.3 Hz), 4.01-4.08(2H,m), 7.56-7.63(2H,m), 7.71(1H, d, J=8.3 Hz), 8.61(3H,br), 9.41(2H,br), 11.90(1H,br)

Example 210 Synthesis of 2-(3-aminophenyl)-2-t-butoxycarbonylaminoacetic acid methyl ester

Using 3-nitrophenylacetic acid as a starting material, the same procedure of Example 78 gave 2.09 g of the titled compound (yield, 27%).

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 3.81(3H,s), 5.20(1H, d, J=7.3 Hz), 5.51-5.66(1H,m), 6.61-6.74(3H,m), 7.09-7.15(1H,m)

MS(m/z) 280(M⁺)

Example 211 Synthesis of 2-t-butoxycarbonylamino-2-(3-(S-methylisothioureido)phenyl)acetic acid methyl ester

Using the compound obtained in Example 210 as a starting material, the same procedure of Example 40 gave 2-t-butoxycarbonylamino-2-(3-thioureido)acetic acid. The resulting compound was dissolved in a mixture of methanol (10 ml) and diethylether (5 ml) and a solution of trimethylsilyldiazomethane (2.0 M) in n-hexane was added at room temperature until the reaction mixture no longer foamed. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 0.15 g of the titled compound (yield, 21%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.44(3H,s), 3.71(3H,s), 4.61(2H,brs), 5.27(1H, d, J=7.6 Hz), 5.56-5.67(1H,m), 6.86-6.92(2H,m), 7.02(1H,d, J=7.9 Hz), 7.24-7.37(1H,m)

FAB-MS(m/z) 354(M⁺+1)

Example 212 Synthesis of 2-amino-2-(3-(S-methylisothioureido)phenyl)acetic acid methyl ester dihydrochloride

Using the compound obtained in Example 211 as a starting material, the same procedure of Example 5 gave 123 mg of the titled compound (yield, 90%).

¹H-NMR(D₂O) δ: 2.70(3H,s), 3.84(3H,s), 5.37(1H,s), 7.30-7.57(3H,m), 7.65-7.71(1H,m)

FAB-MS(m/z) 254(M⁺+1)

Example 213 Synthesis of 2-t-butoxycarbonylamino-3-(3-nitrophenyl)propionic acid

Using 3-nitrophenylalanine as a starting material, the same procedure of Example 63 gave 2.54 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 3.01-3.22(1H,m), 3.25-3.45(1H,m), 4.60-4.73(1H,m), 5.02-5.11(1H,m), 7.45-7.56(2H,m), 8.07-8.14(2H,m)

FAB-MS(m/z) 311(M⁺+1)

Example 214 Synthesis of 2-t-butoxycarbonylamino-3-(3-nitrophenyl)propionic acid methyl ester

Using the compound obtained in Example 213 as a starting material, the same procedure of Example 64 gave 2.7 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 3.12(1H, dd, J=13.9, 6.3 Hz), 3.30(1H, dd, J=13.9, 5.6 Hz), 3.76(3H,s), 4.57-4.68(1H,m), 5.10-5.17(1H,m), 7.46-7.53(2H,m), 7.99-8.04(1H,m), 8.08-8.17(1H,m)

Example 215 Synthesis of 3-(3-aminophenyl)-2-t-butoxcyarbonylaminopropionic acid methyl ester

Using the compound obtained in Example 214 as a starting material, the same procedure of Example 2 gave 1.84 of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.90-3.02(2H,m), 3.62(2H,brs), 3.71(3H,s), 4.47-4.61(1H,m), 4.92-5.00(1H,m), 6.45-6.58(3H,m), 7.04-7.10(1H,m)

Example 216 Synthesis of 2-t-butoxycarbonylamino-3-(3-(S-methylisothioureido)phenyl)propionic acid methyl ester

Using the compound obtained in Example 215 as a starting material, the same procedure of Example 211 gave 0.10 g of the titled compound (yield, 4%).

¹H-NMR(CDCl₃) δ: 1.36(9H,s), 2.46(3H,s), 2.85-2.93(1H,m), 3.08-3.15(1H,m), 3.73(3H,s), 4.57-4.69(2H,m), 4.98-5.01(1H,m), 6.72-6.80(3H,m), 7.19-7.27(1H,m)

Example 217 Synthesis of 2-amino-3-(3-(S-methylisothioureido)phenyl)propionic acid methyl ester dihydrochloride

Using the compound obtained in Example 216 as a starting material, the same procedure of Example 5 gave 33 mg of the titled compound (yield, 81%).

¹H-NMR(D₂O) δ: 2.69(3H,s), 3.30(1H, dd, J=14.5, 7.3 Hz), 3.40(1H, dd, J=14.5, 6.3 Hz), 3.84(3H,s), 4.45-4.50(1H,m), 7.28-7.40(3H,m), 7.54-7.59(1H,m)

Example 218 Synthesis of 3-t-butoxycarbonylamino-2-(4-nitrophenyl)propionic acid methyl ester

Using monomethyl 3-phenylsuccinate as a starting material, the same procedure of Example 1c gave 4.2 g of the titled compound (yield, 40%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 3.53-3.68(2H,m), 3.72(3H,s), 4.00-4.12(1H,m), 4.85-4.95(1H,m), 7.45(2H, d, J=8.6 Hz), 8.20(2H, d, J=8.6 Hz)

Example 219 Synthesis of 2-(4-aminophenyl)-3-t-butoxycarbonylaminopropionic acid methyl ester

Using the compound obtained in Example 218 as a starting material, the same procedure of Example 2 gave 3.1 g of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.48(9H,s), 3.47-3.82(5H,m), 3.72(3H,s), 4.87-4.95(1H,m), 6.68(2H, d, J=8.5 Hz), 7.09(2H, d, J=8.5 Hz)

Example 220 Synthesis of 3-t-butoxycarbonylamino-2-(4-(N′-nitroguanidino)phenyl)propionic acid methyl ester

Using the compound obtained in Example 219 as a starting material, the same procedure of Example 6 gave 0.86 g of the titled compound (yield, 68%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 3.39-3.89(3H,m), 3.66(3H,s), 4.80-4.92(1H,m), 6.23(2H, d, J=8.3 Hz), 7.03(2H, d, J=8.3 Hz)

Example 221 Synthesis of 3-amino-2-(4-(N′-nitroguanidino)phenyl)propionic acid methyl ester hydrochloride

Using the compound obtained in Example 220 as a starting material, the same procedure of Example 5 gave 348 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 3.44(1H, dd, J=13.2, 6.9 Hz), 3.63-3.80(1H,m), 3.76(3H,s), 4.22-4.28(1H,m), 7.48(2H, d, J=8.9 Hz), 7.53(2H, d, J=8.9 Hz)

Example 222 Synthesis of 3-t-butoxycarbonylamino-2-(4-(N′-nitroguanidino)phenyl)propionic acid

A mixture of the compound (0.42 g) obtained in Example 220, 2 N aqueous sodium hydroxide solution (0.6 ml) and methanol (10 ml) was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and a 5% aqueous citric acid solution and ethyl acetate were added to the residue. The organic layer was washed with water, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methanol:methylene chloride=5:95) to give 0.34 g of the titled compound (yield, 84%).

¹H-NMR(DMSO-d₆) δ: 1.35(9H,s), 3.05-3.18(1H,m), 3.32-3.41(3H,m), 3.52-3.58(1H,m), 6.50(2H, d, J=8.6 Hz), 6.88(2H, d, J=8.6 Hz)

Example 223 Synthesis of 3-amino-2-(4-(N′-nitroguanidino)phenyl)propionic acid hydrochloride

Using the compound obtained in Example 222 as a starting material, the same procedure of Example 5 gave 287 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 3.40(1H, dd, J=13.2, 6.9 Hz), 3.67(1H, dd, J=13.2, 7.9 Hz), 4.18(1H, dd, J=7.9, 6.9 Hz), 7.48(2H, d, J=8.9 Hz), 7.55(2H, d, J=8.9 Hz)

Example 224 Synthesis of 3-t-butoxycarbonylamino-2-(4-thioureidophenyl)propionic acid methyl ester

Using the compound obtained in Example 219 as a starting material, the same procedure of Example 120 gave 1.10 g of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.41(9H,s), 3.38-3.70(2H,m), 3.69(3H,s), 3.82-3.97(1H,m), 5.04-5.16(1H,m), 6.57(2H,brs), 7.22(2H, d, J=8.3 Hz), 7.30(2H, d, J=8.3 Hz), 9.00(1H,brs)

MS(m/z) 353(M⁺)

Example 225 Synthesis of 3-t-butoxycarbonylamino-2-(4-(S-ethylisothioureido)phenyl)propionic acid methyl ester

Using the compound obtained in Example 224 as a starting material and also using ethyl iodide as a reagent, the same procedure of Example 29 gave 0.55 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.34(3H, t, J=7.3 Hz), 1.42(9H,s), 2.92-3.08(2H,m), 3.40-3.72(2H,m), 3.67(3H,s), 3.78-3.90(1H,m), 4.67(1H,br), 4.90-5.06(1H,m), 6.78(2H, d, J=7.9 Hz), 7.17(2H, d, J=7.9 Hz)

FAB-MS(m/z) 382(M⁺+1)

Example 226 Synthesis of 3-amino-2-(4-(S-ethylisothioureido)phenyl)propionic acid methyl ester dihydrochloride

Using the compound obtained in Example 225 as a starting material, the same procedure of Example 5 gave 0.199 g of the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 3.24(2H, q, J=7.3 Hz), 3.44(1H, dd, J=13.2, 6.9 Hz), 3.69-3.74(1H,m), 3.76(3H,s), 4.21-4.27(1H,m), 7.44(2H, d, J=8.9 Hz), 7.52(2H, d, J=8.9 Hz)

FAB-MS(m/z) 282(M⁺+1)

Example 227 Synthesis of N-(2-nitrophenylmethyl)phthalimide

Using 2-nitrophenylmethyl bromide as a starting material, the same procedure of Example 117 gave 6.24 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 5.31(2H,s), 7.25-7.27(1H,m), 7.45(1H, t, J=7.6 Hz), 7.55(1H, t, J=7.6 Hz), 7.75-7.94(4H,m), 8.11(1H, d, J=7.9 Hz)

MS(m/z) 282(M⁺)

Example 228 Synthesis of N-(2-nitrophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 227 as a starting material, the same procedure of Example 118 gave 7.59 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 4.57(2H, d, J=6.6 Hz), 5.30-5.43(1H,m), 7.38-7.50(1H,m), 7.62-7.64(2H,m), 8.05(1H, d, J=7.9 Hz)

Exmaple 229 Synthesis of N-(2-aminophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 228 as a starting material, the same procedure of Example 2 gave 4.54 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 4.18(2H, d, J=6.4 Hz), 6.40-6.79(1H,m), 6.85-7.23(2H,m), 7.80(1H, d, J=8.0 Hz)

MS(m/z) 222(M⁺)

Example 230 Synthesis of N-(2-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 229 as a starting material, the same procedure of Example 120 gave 525 mg of the titled compound (yield, 26%).

¹H-NMR(CDCl₃) δ: 1.40(9H,s), 4.26(2H, d, J=5.9 Hz), 5.38-5.57(1H,m), 6.42(2H,brs), 7.28-7.38(4H,m), 9.27(1H,brs)

MS(m/z) 281(M⁺)

Example 231 Synthesis of N-(2-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 230 as a starting material, the same procedure of Example 27 gave 0.60 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.34(3H, t, J=7.3 Hz), 1.43(9H,s), 2.88-3.06(2H,m), 4.15(2H, d, J=4.4 Hz), 4.80(2H,brs), 5.25-5.38(1H,m), 6.80(1H, d, J=7.8 Hz), 6.98(1H, t, J=7.8 Hz), 7.13-7.34(2H,m)

MS(m/z) 309(M⁺)

Example 232 Synthesis of N-(2-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 231 as a starting material, the same procedure of Example 5 gave 451 mg of the titled compound (yield, 86%).

¹H-NMR D₂O) δ: 1.40(3H, t, J=7.3 Hz), 3.24(2H, q, J=7.3 Hz), 4.23(2H,s), 7.47-7.64(4H,m)

FAB-MS(m/z) 210(M⁺+1)

Example 233 Synthesis of N-(1-(3-(N′-t-butoxycarbonyl-N′-ethyl-guanidino)phenyl)cyclohexyl)carbamic acid t-butyl ester

To a mixture of the compound (100 mg) obtained in Example 139, N-ethyl-N′-t-butoxycarbonylthiourea (85 mg) and dimethylformamide (5 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79 mg) at room temperature and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=98:2) to give 156 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.00-1.08(3H,m), 1.27-1.82(8H,m), 1.53(9H,s), 1.62(9H,s), 2.07-2.30(2H,m), 3.32-3.48(2H,m), 4.84 (1H,brs), 6.98-7.40(4H,m), 8.02(1H,s)

Example 234 Synthesis of N-(1-(3-(N′-ethylguanidino)phenyl)cyclohexyl)amine dihydrochloride

Using the compound obtained in Example 233 as a starting material, the same procedure of Example 5 gave 85 mg of the titled compound (yield, 78%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 1.31-1.64(4H,m), 1.64-1.86(2H,m), 1.90-2.06(2H,m), 2.40-2.60(2H,m), 3.33(2H, q, J=7.3 Hz), 7.30-7.77(4H,m)

Example 235 Synthesis of N-(1-(3-(N′-t-butoxycarbonyl-N″-ethyl-guanidino)phenyl)cyclopentyl)carbamic acid t-butyl ester

Using the compound obtained in Example 148 as a starting material, the same procedure of Example 233 gave 160 mg of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.00-1.20(3H,m), 1.34(9H,s), 1.53(9H,s), 1.72-1.92(4H,m), 1.93-2.10(2H,m), 2.12-2.35(2H,m), 3.30-3.50(2H,m), 4.82(1H, brs), 6.90-7.20(4H,m), 8.02(1H,s)

Example 236 Synthesis of N-(1-(3-(N′-ethylguanidino)phenyl)cyclopentyl)amine dihydrochloride

Using the compound obtained in Example 235 as a starting material, the same procedure of Example 5 gave 88 mg of the titled compound (yield, 79%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 1.82-2.06(4H,m), 2.22-2.40(4H,m), 3.33(2H, q, J=7.3 Hz), 7.34-7.61(4H,m)

Example 237 Synthesis of N-(1-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenyl)cyclobutyl)carbamic acid t-butyl ester

Using the compound obtained in Example 157 as a starting material, the same procedure of Example 233 gave 171 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.00-1.21(3H,m), 1.36(9H,s), 1.53(9H,s), 1.65-1.98(1H,m), 2.01-2.22(1H,m), 2.26-2.60(4H,m), 3.35-3.50(2H,m), 5.17(1H,brs), 6.95-7.20(4H,m), 8.01(1H,s)

Example 238 Synthesis of N-(1-(3-(N′-ethylguanidino)phenyl)cyclobutyl)amine dihydrochloride

Using the compound obtained in Example 237 as a starting material, the same procedure of Example 5 gave 85 mg of the titled compound (yield, 73%).

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.3 Hz), 1.94-2.04(1H,m), 2.19-2.24(1H,m), 2.60-2.84(4H,m), 3.33(2H, q, J=7.3 Hz), 7.35-7.63(4H,m)

Example 239 Synthesis of (3-nitro-5-trifluoromethylphenyl)methanol

Using 3-nitro-5-trifluoromethylbenzoic acid as a starting material, the same procedure of Example 132 gave 4.6 g of the titled compound (yield, 98%)

¹H-NMR(CDCl₃) δ: 2.21(1H, t, J=5.6 Hz), 4.92(2H, d, J=5.6 Hz), 7.99(1H,s), 8.41(1H,s), 8.44(1H,s)

Example 240 Synthesis of 3-bromomethyl-5-trifluoromethylnitrobenzene

Using the compound obtained in Example 239 as a starting material, the same procedure of Example 55 gave 7.72 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 4.58(2H,s), 7.99(1H,s), 8.44(1H,s), 8.46(1H,s)

Example 241 Synthesis of N-(3-nitro-5-trifluoromethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 240 as a starting material, the same procedure of Example 127 gave 2.6 g of the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 1.51(18H,s), 4.92(2H,s), 7.93(1H,s), 8.41(2H,s)

Example 242 Synthesis of N-(3-amino-5-trifluoromethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 241 as a starting material, the same procedure of Example 2 gave 2.19 g of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 4.71(2H,s), 6.76-6.90(3H,m)

Example 243 Synthesis of N-(3-thioureido-5-trifluoromethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 242 as a starting material, the same procedure of Example 120 gave 1.02 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 4.82(2H,s), 6.26(2H,brs), 7.45-7.50(3H,m), 8.32(1H,s)

Example 244 Synthesis of N-(3-(S-ethylisothioureido)-5-trifluoromethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 243 as a starting material, the same procedure of Example 95 gave 99 mg of the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=7.3 Hz), 1.47(18H,s), 2.90-3.12(2H,m), 4.78(2H,s), 7.00-7.22(3H,m)

Example 245 Synthesis of N-(3-(S-ethylisothioureido)-5-trifluoromethylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 244 as a starting material, the same procedure of Example 5 gave 81 mg of the titled compound (yield, 88%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.26(2H, q, J=7.3 Hz), 4.33(2H,s), 7.72(1H,s), 7.83(1H,s), 7.89(1H,s)

Example 246 Synthesis of N-(3-(N′-nitroguanidino)-5-trifluoromethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 242 as a starting material, the same procedure of Example 6 gave 17.2 mg of the titled compound (yield, 5.6%).

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 4.84(2H,s), 7.50-7.60(3H,m), 9.79(1H,s)

Example 247 Synthesis of N-(3-(N′-nitroguanidino)-5-trifluoromethylphenylmethyl)amine hydrochloride

Using the compound obtained in Example 246 as a starting material, the same procedure of Example 5 gave 81 mg of the titled compound (yield, 88%).

¹H-NMR(D₂O) δ: 4.29(2H,s), 7.68-7.78(3H,m)

Example 248 Synthesis of N-(3-fluoro-4-methylphenyl)phthalimide

A mixture of 3-fluoro-4-methylaniline (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated under reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the resulting residue and the insoluble matter was filtered off whereas the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=98:2) to give 18.7 g of the titled compound (yield, 73%).

¹H-NMR(CDCl₃) δ: 2.33(3H,s), 7.14(1H,s), 7.18(1H,s), 7.28-7.34(1H,m), 7.79-7.82(2H,m), 7.94-7.98(2H,m)

Example 249 Synthesis of N-(4-bromomethyl-3-fluorophenyl)phthalimide

A mixture of the compound (1.0 g) obtained in Example 248, N-bromosuccinimide (698 mg), α,α′-azobis(isobutyronitrile) (catalytic amount) and carbon tetrachloride (20 ml) was heated under reflux for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=8:2) to give 605 mg of the titled compound (yield, 46%).

¹H-NMR(CDCl₃) δ: 4.55(2H,s), 7.28-7.33(2H,m), 7.50-7.56(1H,m), 7.80-7.84(2H,m), 7.96-7.99(2H,m)

Example 250 Synthesis of N-(4-cyanomethyl-3-fluorophenyl)phthalimide

To a solution of sodium cyanide (99 mg) in dimethyl sulfoxide (5 ml), a solution of the compound (605 mg) obtained in Example 249 in dimethyl sulfoxide (10 ml) was added dropwise at 60° C. and stirred at 60° C. for 40 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate-diethyl ether (1:1); thereafter, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 164 mg of the titled compound (yield, 32%).

¹H-NMR(CDCl₃) δ: 3.83(2H,s), 7.33-7.41(2H,m), 7.57-7.63(1H,m), 7.81-7.84(2H,m), 7.96-8.00(2H,m)

Example 251 Synthesis of 4-cyanomethyl-3-fluoroaniline

To a solution of the compound (164 mg) obtained in Example 250 in methanol (5 ml), hydrazine monohydrate (0.057 ml) was added and heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 67 mg of the titled compound (yield, 76%).

¹H-NMR(CDCl₃) δ: 3.62(2H,s), 3.84(2H,brs), 6.37-6.47(2H,m), 7.09-7.16(1H,m)

Example 252 Synthesis of 4-(2-aminoethyl)-3-fluoroaniline

To a suspension of aluminum lithium hydride (76 mg) in diethyl ether (5 ml), conc. sulfuric acid (0.053 ml) was added under ice cooling and stirred at room temperature for 1 h. Subsequently, a solution of the compound (100 mg) obtained in Example 251 in diethyl ether (15 ml) was added dropwise at room temperature and heated under reflux for 18 h. To the reaction mixture, water (1 ml) and 2 N aqueous sodium hydroxide solution (10 ml) were added under ice cooling and the mixture was extracted with diethyl ether; the organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 110 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 2.65(2H, t, J=6.9 Hz), 2.88(2H, t, J=6.9 Hz), 3.70(2H, brs), 6.34-6.42(2H,m), 6.91-6.98(1H,m)

Example 253 Synthesis of N-(2-(4-amino-2-fluorophenyl)ethyl)carbamic acid t-butyl ester

To a solution of the compound (110 mg) obtained in Example 252 in methylene chloride (10 ml), di-t-butyl dicarbonate (113 mg) was added under ice cooling and stirred for 1 h under ice cooling. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=6:4) to give 51 mg of the titled compound (yield, 39%)

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 2.70(2H, t, J=6.9 Hz), 3.22-3.38(2H,m) 3.70(2H,brs), 4.58(1H,brs), 6.34-6.40(2H,m), 6.90-6.96(1H,m)

Example 254 Synthesis of N-(2-(2-fluoro-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 253 as a starting material, the same procedure of Example 120 gave 172 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.84(2H, t, J=6.9 Hz), 3.30-3.44(2H,m), 4.63(1H,brs), 6.19(2H,brs), 6.95-6.99(2H,m), 7.20-7.35(1H,m), 8.10(1H,brs)

Example 255 Synthesis of N-(2-(4-(S-ethylisothioureido)-2-fluorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 254 as a starting material, the same procedure of Example 95 gave 151 mg of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=7.3 Hz), 1.43(9H,s), 2.78(2H, t, J=6.9 Hz), 2.92-3.15(2H,m), 3.28-3.40(2H,m), 4.58(1H,brs), 6.60-6.70(2H,m), 7.07-7.13(1H,m)

Example 256 Synthesis of N-(2-(4-(S-ethylisothioureido)-2-fluorophenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 255 as a starting material, the same procedure of Example 5 gave 141 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 3.09(2H, t, J=7.3 Hz), 3.23(2H, q, J=7.3 Hz), 3.29(2H, t, J=7.3 Hz), 7.19-7.24(2H,m), 7.45-7.52(1H,m)

Example 257 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-fluorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 253 as a starting material, the same procedure of Example 233 gave 167 mg of the titled compound (yield, 76%).

¹H-NMR(CDCl₃) δ: 1.19(3H, t, J=7.3 Hz), 1.43(9H,s), 1.48(9H,s), 2.70-2.86(2H,m), 3.22-3.48(4H,m), 5.94(1H,brs), 6.50-7.22 (3H,m), 8.02(1H,s)

Example 258 Synthesis of N-(2-(4-(N′-ethylguanidino)-2-fluorophenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 257 as a starting material, the same procedure of Example 5 gave 75 mg of the titled compound (yield, 67%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 3.07(2H, t, J=7.3 Hz), 3,27-3.36(4H,m), 7.11-7.45(3H,m)

Example 259 Synthesis of N-(2-(2-fluoro-4-(N′-nitroguanidino)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 253 as a starting material, the same procedure of Example 6 gave 65 mg of the titled compound (yield, 48%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 2.87(2H, t, J=6.6 Hz), 3.30-3.46(2H,m), 4.69(1H,brs), 7.00-7.12(2H,m), 7.28-7.40(1H,m), 9.84(1H,s)

Example 260 Synthesis of N-(2-(2-fluoro-4-(N′-nitroguanidino)phenyl)ethyl)amine hydrochloride

Using the compound obtained in Example 259 as a starting material, the same procedure of Example 5 gave 28 mg of the titled compound (yield, 57%).

¹H-NMR(D₂O) δ: 3.07(2H, t, J=7.3 Hz), 3.30(2H, t, J=7.3 Hz), 7.15-7.45(3H,m)

Example 261 Synthesis of 2-fluoro-5-nitrobenzyl alcohol

Using 2-fluoro-5-nitrobenzoic acid as a starting material, the same procedure of Example 132 gave the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 2.10(1H, t, J=5.9 Hz), 4.86(2H, d, J=5.9 Hz), 7.16-7.24(1H,m), 8.15-8.25(1H,m), 8.40-8.47(1H,m)

Example 262 Synthesis of 2-fluoro-5-nitrobenzyl bromide

Using the compound obtained in Example 261 as a starting material, the same procedure of Example 55 gave the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 4.53(2H,s), 7.22-7.30(1H,m), 8.18-8.27(1H,m), 8.40-8.47(1H,m)

MS(m/Z) 234(M⁺)

Example 263 Synthesis of N-(2-fluoro-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 262 as a starting material, the same procedure of Example 127 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.50(18H,s), 4.91(2H,s), 7.15-7.22(1H,m), 8.12-8.21(2H,m)

Example 264 Synthesis of N-(2-dimethylamino-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

A mixture of the compound (1.0 g) obtained in Example 263, dimethylamine hydrochloride (485 mg), triethylamine (0.8 ml) and dimethylformamide (10 ml) was heated at 80° C. for 5.5 h. The reaction mixture was distilled under reduced pressure and water and 2 N HCl were added to the residue; after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.1 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.39(18H,s), 2.78(6H,s), 4.78(2H,s), 6.97(1H, d, J=8.6 Hz), 7.95-8.02(2H,m)

Example 265 Synthesis of N-(5-amino-2-dimethylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 264 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.42(18H,s), 2.58(6H,s), 3.48(2H,brs), 4.85(2H,s), 6.43-6.54(2H,m), 6.94(1H, d, J=8.3 Hz)

MS(m/z) 365(M⁺+1)

Example 266 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)2-dimethylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 265 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 73%).

¹H-NMR (CDCl₃) δ: 1.08-1.12(3H,m), 1.43(18H,s), 1.53(9H,s), 2.68(6H,s), 3.10-3.48(2H,m), 4.85(2H,s), 6.84-7.12(3H,m)

MS(m/z) 535(M⁺)

Example 267 Synthesis of N-(2-dimethylamino-5-(N′-ethylguanidino)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 266 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 67%).

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.3 Hz), 3.24(6H,s), 3.35(2H, q, J=7.3 Hz), 4.41(2H,s), 7.49-7.58(2H,m), 7.82(1H, d, J=8.9 Hz)

MS(m/z) 235(M⁺)

Example 268 Synthesis of N-(2-dimethylamino-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 265 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.44(18H,s), 2.68(6H,s), 4.84(2H,s), 6.22(2H,brs), 6.92-7.00(1H,m), 7.04-7.16(2H,m), 8.25(1H,brs)

MS(m/z) 424(M⁺)

Example 269 Synthesis of N-(2-dimethylamino-5-(S-ethylisothioureido)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 268 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ1.34(3H, t, J=7.3 Hz), 1.42(18H,s), 2.63(6H,s), 2.83-3.13(2H,m), 4.87(2H,s), 6.69-7.06(3H,m)

MS(m/z) 452(M⁺)

Example 270 Synthesis of N-(2-dimethylamino-5-(S-ethylisothioureido)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 269 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 67%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.3 Hz), 3.27(2H, q, J=7.3 Hz), 3.33(6H,s), 4.48(2H,s), 7.66(1H, d,J=2.3 Hz), 7.72(1H, dd, J=8.6, 2.3 Hz), 7.97(1H, d, J=8.6 Hz)

MS(m/z) 252(M⁺)

Example 271 Synthesis of N-(2-methoxy-5-(N′-nitroguanidino)phenylmethyl)carbamic acid t-butyl ester

A mixture of the compound (130 mg) obtained in Example 119, triethylamine (0.09 ml), S-methyl-N-nitroisothiourea (84 mg), acetonitrile (3 ml) and methanol (1 ml) was heated under reflux for 20 h. The reaction mixture was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=1:1) to give 57.2 mg of the titled compound (yield, 33%).

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 3.87(3H,s), 4.28(2H, d, J=5.9 Hz), 5.20(1H,brs), 6.91(1H, d, J=9.3 Hz), 7.19-7.28(2H,m), 9.28(1H,brs)

Example 272 Synthesis of N-(2-methoxy-5-(N′-nitroguanidino)phenylmethyl)amine hydrochloride

Using the compound obtained in Example 271 as a starting material, the same procedure of Example 5 gave 41 mg of the titled compound (yield, 90%).

¹H-NMR(D₂O) δ: 3.95(3H,s), 4.20(2H,s), 7.18(1H, d, J=8.9 Hz), 7.34(1H, d, J=2.6 Hz), 7.41(1H, dd, J=8.9, 2.6 Hz)

Example 273 Synthesis of N-(5-(N′-t-butoxycarbonyl-N-ethylguanidino)-2-methoxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 119 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.00-1.20(3H,m), 1.44(9H,s), 1.53(9H,s), 3.30-3.50(2H,m), 3.85(3H,s), 4.28(2H,brs), 5.00(1H,brs), 6.80-7.20(3H,m)

Example 274 Synthesis of N-(5-(N′-ethylguanidino)-2-methoxyphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 273 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 95%).

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 3.29(2H, q, J=7.3 Hz), 3.93(3H,s), 4.17(2H,s), 7.16(1H, d, J=8.9 Hz), 7.28(1H, d, J=2.6 Hz), 7.38(1H, dd, J=8.9, 2.6 Hz)

MS(m/z) 222(M⁺)

Example 275 Synthesis of N-(2-methoxy-5-(N′-methylguanidino)phenylmethyl)carbamic acid t-butyl ester

The compound obtained in Example 121 was dissolved in ethyl acetate and the solution was washed with a saturated aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. A mixture of the resulting residue (150 mg), methylamine hydrochloride (33 mg), triethylamine (0.13 ml) and dimethylformamide (6 ml) was stirred at 80° C. for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=6:1) to give 106.1 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.40(9H,s), 2.96(3H, d, J=3.9 Hz), 3.83(3H,s), 4.20(2H, d, J=5.9 Hz), 5.50(1H, brs), 6.85(1H, d, J=9.3 Hz), 7.00-7.20(2H,m), 9.54(1H,brs)

MS(m/z) 308(M⁺)

Example 276 Synthesis of N-(2-methoxy-5-(N′-methylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 275 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 55%).

¹H-NMR(D₂O) δ: 2.88(3H,s), 3.93(3H,s), 4.17(2H,s), 7.16(1H, d, J=8.9 Hz), 7.28(1H, d, J=2.6 Hz), 7.38(1H, dd, J=8.9, 2.6 Hz)

MS(m/z) 208(M⁺)

Example 277 Synthesis of N-(3-(t-butoxycarbonylaminomethyl)-4-methoxyphenyl)amidinosulfonic acid

To a mixture of the compound (327 mg) obtained in Example 120, sodium molybdate dehydrate (25 mg), methanol (10 ml) and water (10 ml), aqueous hydrogen peroxide (0.3 ml) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 1.5 h, and methanol was distilled off under reduced pressure. The resulting suspension was collected by filtration, washed with water and dried under reduced pressure to give 335 mg of the titled compound (yield, 93%).

¹H-NMR(DMSO-d₆) δ: 1.40(9H,s), 3.83(3H,s), 4.12(2H, d, J=5.9 Hz), 7.03-7.19(3H,m), 8.98(1H,brs), 9.50(1H,brs), 11.30(1H,brs)

Example 278 Synthesis of N-(2-methoxy-5-(N′-n-propylguanidino)phenylmethyl)carbamic acid t-butyl ester

To a solution of the compound (160 mg) obtained in Example 277 in acetonitrile (5 ml), n-propylamine (0.05 ml) was added dropwise and stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure and 2 N aqueous sodium hydroxide solution was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:2) to give 160 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 0.93(3H, t, J=7.3 Hz), 1.42(9H,s), 1.49-1.59(2H,m), 3.15(2H, t, J=7.3 Hz), 3.80(3H,s), 4.22(2H,brs), 4.92(1H,brs), 6.75-6.86(3H,m)

MS(m/z) 336(M⁺)

Example 279 Synthesis of N-(2-methoxy-5-(N′-n-propylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 278 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 71%).

¹H-NMR(D₂O) δ: 0.93(3H, t, J=7.3 Hz), 1.55-1.68(2H,m), 3.22(2H, t, J=7.3 Hz), 3.93(3H,s), 4.17(2H,s), 7.16(1H, d, J=8.6 Hz), 7.28(1H, d, J=2.6 Hz), 7.38(1H, dd, J=8.6, 2.6 Hz)

MS(m/z) 236(M⁺)

Example 280 Synthesis of N-(2-dimethylamino-5-(N′-nitroguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 265 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 52%). 1H-NMR(CDCl₃) δ: 1.43(18H,s), 2.71(6H,s), 4.86(2H,s), 7.02-7.16(3H,m), 9.82(1H,brs)

Example 281 Synthesis of N-(2-dimethylamino-5-(N′-nitroguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 280 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 3.13(6H,s), 4.38(2H,s), 7.51-7.55(2H,m), 7.73(1H, dd, J=7.9, 1.3 Hz)

Example 282 Synthesis of N-(2-(N-ethyl-N-methylamino)-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using ethylmethylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 42%).

¹H-NMR(CDCl₃) δ: 1.18(3H, t, J=7.2 Hz), 1.45(18H,s), 2.81(3H,s), 3.05(2H, q, J=7.2 Hz), 4.82(2H,s), 7.06(1H, d, J=8.2 Hz), 8.04-8.15(2H,m)

Example 283 Synthesis of N-(5-amino-2-(N-ethyl-N-methylamino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 282 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 58%).

¹H-NMR(CDCl₃) δ: 1.04(3H, t, J=7.0 Hz), 1.42(18H,s), 2.56(3H,s), 2.79(2H, q, J=7.0 Hz), 3.55(2H, brs), 4.84(2H,s), 6.43-6.56(3H,m)

MS(m/z) 379(M⁺)

Example 284 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-(N-ethyl-N-methylamino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 283 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 77%).

¹H-NMR(CDCl₃) δ: 1.09(3H, t, J=7.2 Hz), 1.29-2.66(21H,m), 2.65(3H,s), 2.86(2H, q, J=7.2 Hz), 3.30-3.50(2H,m), 4.84(2H,s), 6.80-7.11(3H,m)

MS(m/z) 549(M⁺)

Example 285 Synthesis of N-(5-(N′-ethylguanidino)-2-(N-ethyl-N-methyl-amino)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 284 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 1.15-1.26(6H,m), 3.21(3H,s), 3.26-3.38(2H,m), 3.54-3.65(2H,m), 4.39(2H,s), 7.35-7.57(2H,m), 7.75(1H, d, J=8.6 Hz)

Example 286 Synthesis of N-(2-(N-ethyl-N-methylamino)-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 283 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 77%).

¹H-NMR(CDCl₃) δ: 1.14(3H, t, J=7.1 Hz), 1.45(18H,s), 2.66(3H,s), 2.89(2H, q, J=7.1 Hz), 4.83(2H, s), 6.15(2H,brs), 6.94-7.14(3H,m), 8.00(1H,brs)

MS(m/z) 439(M⁺+1)

Example 287 Synthesis of N-(5-(S-ethylisothioureido)-2-(N-ethyl-N-methylamino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 286 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 66%).

¹H-NMR(CDCl₃) δ: 1.04(3H, t, J=7.2 Hz), 1.31-1.45(21H,m), 2.61(3H,s), 2.83(2H, q, J=7.2 Hz), 3.00-3.20(2H,m), 4.47(1H,brs), 4.86(2H,s), 6.60-6.85(2H,m), 7.05(1H, d, J=8.2 Hz)

MS(m/z) 466(M⁺)

Example 288 Synthesis of N-(5-(S-ethylisothioureido)-2-(N-ethyl-N-methylamino)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 287 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 95%).

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.3 Hz), 1.43(3H, t, J=7.3 Hz), 3.27(2H, q, J=7.3 Hz), 3.37(3H,s), 3.72(2H, q, J=7.3 Hz), 4.51(2H,s), 7.69(1H, d, J=2.3 Hz), 7.74(1H, dd, J=8.6, 2.3 Hz), 7.94(1H, d, J=8.6 Hz)

MS(m/z) 266(M⁺)

Example 289 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-S-methylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester

To a mixture of the compound (280 mg) obtained in Example 51, sodium bicarbonate (87 mg) and methylene chloride (5 ml), di-t-butyl dicarbonate (227 mg) was added and stirred at room temperature for 15 h; thereafter, methylene chloride and water were added. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 303 mg of the titled compound (yield, 81%).

¹H-NMR (CDCl₃) δ: 1.26-1.56(18H,m), 2.40(3H,s), 2.77-2.80(2H,m), 3.35-3.38(2H,m), 4.69(1H,brs), 7.20(4H,s), 11.28(1H,brs)

Example 290 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-methoxyguanidino)phenyl)ethyl)carbamic acid t-butyl ester

To a mixture of the compound (190 mg) obtained in Example 289, triethylamine (0.14 ml), O-methylhydroxylamine hydrochloride (84 mg) and acetonitrile (5 ml), a solution of silver nitrate (90 mg) in acetonitrile (2 ml) was added and stirred at 0° C. for 15 min. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=3:1) to give the 75 mg of titled compound (yield, 38%).

¹H-NMR(CDCl₃) δ: 1.43(9H,s), 1.51(9H,s), 2.72(2H, t, J=6.9 Hz), 3.32-3.35(2H,m), 3.80(3H,s), 4.53(1H,brs), 7.08(2H, d, J=8.5 Hz), 7.40(2H, d, J=8.5 Hz), 7.85(1H,brs), 8.88(1H,brs)

MS(m/z) 408(M⁺)

Example 291 Synthesis of N-(2-(4-(N′-methoxyguanidino)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 290 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 3.04(2H, t, J=7.2 Hz), 3.29(2H, t, J=7.2 Hz), 3.81(3H,s), 7.30(2H, d, J=8.6 Hz), 7.42(2H, d, J=8.6 Hz)

MS(m/z) 208(M⁺)

Example 292 Synthesis of (2,6-dimethoxy-3-nitrophenyl)methanol

Using 2,6-dimethoxy-3-nitrobenzoic acid as a starting material, the same procedure of Example 132 gave the titled compound (yield, 39%).

¹H-NMR(CDCl₃) δ: 3.98(6H,s), 4.79(2H,s), 6.75(1H, d, J=9.2 Hz), 7.99(1H, d, J=9.2 Hz)

Example 293 Synthesis of 2,6-dimethoxy-3-nitrobenzyl bromide

Using the compound obtained in Example 292 as a starting material, the same procedure of Example 55 gave the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 4.00(3H,s), 4.02(3H,s), 4.62(2H,s), 6.74(1H, d, J=9.2 Hz), 8.02(1H, d, J=9.2 Hz)

MS(m/z) 276(M⁺)

Example 294 Synthesis of N-(2,6-dimethoxy-3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 293 as a starting material, the same procedure of Example 127 gave the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.44-1.48(18H,m), 3.86(3H,s), 3.88(3H,s), 4.94(2H,s), 6.68(1H, d, J=9.2 Hz), 7.93(1H, d, J=9.2 Hz)

Example 295 Synthesis of N-(3-amino-2,6-dimethoxyphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 294 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 45%).

¹H-NMR(CDCl₃) δ: 1.42(18H,s), 3.50(2H,brs), 3.70(6H,s), 4.91(2H,s), 6.56(1H, d, J=8.3 Hz), 6.63(1H, d, J=8.3 Hz)

MS(m/z) 382(M⁺)

Example 296 Synthesis of N-(2,6-dimethoxy-3-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 295 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 46%).

¹H-NMR(CDCl₃) δ: 1.44(18H,s), 3.79(3H,s), 3.81(3H,s), 4.89(2H,s), 6.11(2H,brs), 6.66(1H, d, J=8.9 Hz), 7.12(1H, d, J=8.9 Hz), 7.63(1H,brs)

MS(m/z) 441(M⁺)

Example 297 Synthesis of N-(2,6-dimethoxy-3-(S-ethylisothioureido)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 296 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.35-1.51(21H,m), 3.00-3.12(2H,m), 3.70(3H,s), 3.76(3H,s), 4.58(1H,brs), 4.91(2H,s), 6.58(1H, d, J=8.9 Hz), 6.75-6.78(1H,m)

MS(m/z) 469(M⁺)

Example 298 Synthesis of N-(2,6-dimethoxy-3-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 297 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.3 Hz), 3.34(2H, q, J=7.3 Hz), 3.63(3H,s), 3.66(3H,s), 4.28(2H,s), 7.01(1H, d, J=8.9 Hz), 7.42(1H, d, J=8.9 Hz)

MS(m/z) 269(M⁺)

Example 299 Synthesis of N-(1-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 2 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.11-1.60(27H,m), 3.30-3.40(2H,m), 5.00(2H,s), 7.00-7.34(4H,m)

MS(m/z) 420(M⁺)

Example 300 Synthesis of N-(1-(3-(N′-ethylguanidino)phenyl)-1-methylethyl) amine dihydrochloride

Using the compound obtained in Example 299 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.3 Hz), 1.77(6H,s), 3.33(2H, q, J=7.3 Hz), 7.36-7.68(4H,m)

MS(m/z) 220(M⁺)

Example 301 Synthesis of N-(3-(di-(t-butoxycarbonyl)aminomethyl)phenyl)amidinosulfonic acid

Using N-(3-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester as a starting material, the same procedure of Example 277 gave the titled compound (yield, 98%).

¹H-NMR(DMSO-d₆) δ: 1.42(18H,s), 4.71(2H,s), 7.15-7.24(3H,m), 7.43-7.49(1H,m), 9.61(1H,brs), 11.50(1H,brs)

Example 302 Synthesis of N-(3-(N′,N′-dimethylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 301 as a starting material and also using dimethylamine hydrochloride and triethylamine as reagents, the same procedure of Example 278 gave the titled compound (yield, 50%).

¹H-NMR(CDCl₃) δ: 1.45(18H,s), 2.98(6H,s), 4.73(2H,s), 6.75-6.87(3H,m), 7.16-7.19(1H,m)

MS(m/z) 392(M⁺)

Example 303 Synthesis of N-(3-(N′,N′-dimethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 302 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 96%).

¹H-NMR(D₂O) δ: 3.14(6H,s), 4.19(2H,s), 7.31-7.57(4H,m)

MS(m/z) 192(M⁺)

Example 304 Synthesis of N-(3-(N′-ethyl-N′-methylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 301 as a starting material and also using ethylmethylamine as a reagent, the same procedure of Example 278 gave the titled compound (yield, 27%).

¹H-NMR(CDCl₃) δ: 1.17(3H, t, J=7.3 Hz), 1.45(18H,s), 2.95(3H,s), 3.38(2H, q, J=7.3 Hz), 4.73(2H,s), 6.75-7.19(4H,m)

MS(m/z) 406(M⁺)

Example 305 Synthesis of N-(3-(N′-ethyl-N′-methylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 304 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.28(3H, t, J=7.3 Hz), 3.12(3H,s), 3.53(2H, q, J=7.3 Hz), 4.23(2H,s), 7.30-7.70(4H,m)

MS(m/z) 206(M⁺)

Example 306 Synthesis of N-(3-(N′-(2-propynyl)guanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 301 as a starting material and also using propargylamine as reagent, the same procedure of Example 278 gave the titled compound (yield, 55%).

¹H-NMR(CDCl₃) δ: 1.45(18H,s), 2.26(1H,s), 4.04(2H,s), 4.73(2H,s), 6.78-6.90(3H,m), 7.21(1H, dd, J=7.6, 7.6 Hz)

MS(m/z) 402(M⁺)

Example 307 Synthesis of N-(3-(N′-(2-propynyl)guanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 306 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 2.81(1H, t, J=2.6 Hz), 4.15(2H, d, J=2.6 Hz), 4.24(2H,s), 7.28-7.41(2H,m), 7.47(1H, d, J=7.9 Hz), 7.58(1H, dd, J=7.9, 7.9 Hz)

MS(m/z) 202(M⁺)

Example 308 Synthesis of N-(2-nitrophenylethyl)phthalimide

Using 2-nitrophenethyl alcohol as a starting material, the same procedure of Example 179 gave the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 3.31(2H, t, J=6.9 Hz), 4.10(2H, t, J=6.9 Hz), 7.28-7.50(3H,m), 7.68-7.74(2H,m), 7.77-7.84(2H,m), 7.96-8.20(1H,m)

Example 309 Synthesis of N-(2-nitrophenylethyl)carbamic acid t-butyl ester

Using the compound (2.18 g) obtained in Example 308 as a starting material, the same procedure of Example 180 gave 2-nitrophenylethylamine. A two-layered mixture consisting of the resulting amine compound, di-t-butyl dicarbonate (1.77 g), methylene chloride (120 ml) and 2 N aqueous sodium hydroxide solution (30 ml) was stirred at room temperature for 14 h. The organic layer was dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.95 g of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 3.09(2H, t, J=6.6 Hz), 3.46(2H, dt, J=6.6, 6.6 Hz), 4.70(1H,brs), 7.34-7.43(2H,m), 7.50-7.59(1H,m), 7.91-7.97(1H,m)

MS(m/z) 266(M⁺)

Example 310 Synthesis of N-(2-aminophenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 309 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 2.70(2H, t, J=6.9 Hz), 3.28(2H, dt, J=6.9, 6.9 Hz), 3.93(2H,brs), 4.87(1H,brs), 6.64-6.74(2H,m), 6.96-7.09(2H,m)

MS(m/z) 236(M⁺)

Example 311 Synthesis of N-(2-thioureidophenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 310 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 2.80(2H, t, J=6.9 Hz), 3.32(2H, dt, J=6.9, 6.9 Hz), 4.80(1H,brs), 6.28(2H,brs), 7.20-7.28(4H,m)

MS(m/z) 295(M⁺)

Example 312 Synthesis of N-(2-(S-ethylisothioureido)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 311 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.33-1.40(3H,m), 1.39(9H,s), 2.69(2H, t, J=6.3 Hz), 3.00-3.20(2H,m), 3.32(2H, dt, J=6.3, 6.3 Hz), 4.56(2H,brs), 5.27(1H,brs), 6.80-6.88(1H,m), 6.95-7.05(1H,m), 7.12-7.24(2H,m)

MS(m/z) 323(M⁺)

Example 313 Synthesis of N-(2-(S-ethylisothioureido)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 312 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 81%).

¹H-NMR(D₂O) δ: 1.35-1.50(3H,m), 2.99(2H, t, J=7.3 Hz), 3.20-3.33(4H,m), 7.36-7.42(1H,m), 7.44-7.60(3H,m)

Example 314 Synthesis of N-(5-amino-2-fluorophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.45(18H,s), 3.50(2H,brs), 4.78(2H,s), 6.47-6.54(2H,m), 6.77-6.85(1H,m)

Example 315 Synthesis of N-(2-fluoro-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 314 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 4.84(2H,s), 6.11(2H,brs), 7.09-7.14(3H,m), 8.06(1H,brs)

Example 316 Synthesis of N-(5-(S-ethylisothioureido)-2-fluorophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 315 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 53%).

¹H-NMR(CDCl₃) δ: 1.33-1.39(3H,m), 1.45(9H,s), 3.00-3.17(2H,m), 4.32(2H, d, J=5.6 Hz), 4.49(1H,brs), 4.85(1H,brs), 6.71-7.01(4H,m)

MS(m/z) 327(M⁺)

Example 317 Synthesis of N-(5-(S-ethylisothioureido)-2-fluorophenylmethyl)amine dihydrochloride

Using the compound obtained in Example 316 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 3.20-3.28(2H,m), 4.29(2H,s), 7.39-7.53(3H,m)

MS(m/z) 227(M⁺)

Example 318 Synthesis of N-(2-hydroxy-5-nitrophenylmethyl)phthalimide

To a solution of the compound (937 mg) obtained in Example 117 in anhydrous methylene chloride (30 ml), a solution of boron tribromide in methylene chloride (1.0 M, 9 ml) was added dropwise at −78° C. in a nitrogen atmosphere and the mixture was stirred at −78° C. for 1 h, then stirred at room temperature for 21 h. Water was added to the reaction mixture, which was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 743 mg of the titled compound (yield, 83%).

¹H-NMR(CDCl₃) δ: 4.84(2H,s), 6.99(1H, d, J=9.2 Hz), 7.85-7.92(4H,m), 7.95(1H, dd, J=9.2, 2.6 Hz), 8.06(1H, dd, J=9.2, 2.6 Hz), 11.4(1H,s)

MS(m/z) 298(M⁺)

Example 319 Synthesis of N-(2-ethoxy-5-nitrophenylmethyl)phthalimide

To a mixture of sodium hydride (content, 60%; 36 mg) and anhydrous dimethylformamide (5 ml), a solution of the compound (224 mg) obtained in Example 318 in anhydrous dimethylformamide (3 ml) and ethyl iodide (0.072 ml) were successively added dropwise at 0° C. in a nitrogen atmosphere and stirred at room temperature for 24 h. Water was added to the reaction mixture, which was distilled under reduced pressure; thereafter, ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane ethyl acetate=1:1) to give 213 mg of the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.47(3H, t, J=7.3 Hz), 4.17(2H, q, J=7.3 Hz), 4.93(2H,s), 6.90(1H, d, J=9.2 Hz), 7.74-7.91(4H,m), 8.05(1H, d, J=2.6 Hz), 8.17(1H, dd, J=9.2, 2.6 Hz)

MS(m/z) 326(M⁺)

Example 320 Synthesis of N-(2-ethoxy-5-nitrophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 319 as a starting material, the same procedure of Example 309 gave the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 1.49(3H, t, J=7.3 Hz), 4.17(2H, q, J=7.3 Hz), 4.36(2H, d, J=5.9 Hz), 4.98(1H,brs), 6.86-6.91(1H,m), 8.14-8.17(2H,m)

Example 321 Synthesis of N-(5-amino-2-ethoxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 320 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 75%).

¹H-NMR(CDCl₃) δ: 1.38(3H, t, J=6.9 Hz), 1.44(9H,s), 3.41(2H,brs), 3.97(2H, q, J=6.9 Hz), 4.23(2H, d, J=5.9 Hz), 5.00(1H,brs), 6.55(1H, dd, J=8.6, 3.0 Hz), 6.66-6.69(2H,m)

Example 322 Synthesis of N-(2-ethoxy-5-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 321 as a starting material, the same procedure of Example 120 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.44(3H, t, J=7.3 Hz), 1.44(9H,s), 4.07(2H, q, J=7.3 Hz), 4.28(2H, d, J=6.3 Hz), 5.03(1H,brs), 6.04(2H,brs), 6.85(1H, d, J=8.6 Hz), 7.07-7.16(2H,m), 7.85(1H,brs)

MS(m/z) 325(M⁺)

Example 323 Synthesis of N-(2-ethoxy-5-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 322 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 90%).

¹H-NMR(CDCl₃) δ: 1.38(6H, t, J=7.6 Hz), 1.45(9H,s), 3.22(2H, q, J=7.6 Hz), 4.07(2H, q, J=7.6 Hz), 4.28-4.29(2H,m), 5.02(1H,brs), 6.84(1H, d, J=8.6 Hz), 7.06-7.10(2H,m)

MS(m/z) 353(M⁺)

Example 324 Synthesis of N-(2-ethoxy-5-(S-ethylisothioureido)phenylmethyl) amine dihydrochloride

Using the compound obtained in Example 323 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.41(3H, t, J=6.9 Hz), 1.43(3H, t, J=6.9 Hz), 3.15-3.30(2H,m), 4.16-4.31(4H,m), 7.20(1H, d, J=8.9 Hz), 7.34(1H, d, J=2.6 Hz), 7.42(1H, dd, J=8.9, 2.6 Hz)

MS(m/z) 253(M⁺)

Example 325 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-ethoxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 321 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 90%).

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=7.3 Hz), 1.40-1.47(3H,m), 1.45(9H,s), 1.53(9H,s), 3.33-3.43(2H,m), 4.06(2H, q, J=7.3 Hz), 4.16(2H, d, J=5.9 Hz), 4.97(1H,brs), 6.83(1H, d, J=8.3 Hz), 7.04-7.12(2H,m)

Example 326 Synthesis of N-(2-ethoxy-5-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 325 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 1.43(3H, t, J=6.9 Hz), 3.29(2H, q, J=7.3 Hz), 4.17-4.28(4H,m), 7.16(1H, d, J=8.9 Hz), 7.29(1H, d, J=2.6 Hz), 7.36(1H, dd, J=8.9, 2.6 Hz)

MS(m/z) 236(M⁺)

Example 327 Synthesis of N-(2-ethoxy-5-(N′-nitroguanidino)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 321 as a starting material, the same procedure of Example 6 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 1.44-1.48(3H,m), 4.05-4.11(2H,m), 4.30(2H, d, J=3.0 Hz), 5.08(1H,brs), 6.88-6.93(1H,m), 7.16-7.27(2H,m), 9.63(1H,brs)

MS(m/z) 353(M⁺)

Example 328 Synthesis of N-(2-ethoxy-5-(N′-nitroguanidino)phenylmethyl)amine hydrochloride

Using the compound obtained in Example 327 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 95%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=6.9 Hz), 4.19-4.29(4H,m), 7.17(1H, d, J=8.6 Hz), 7.34(1H, d, J=2.6 Hz), 7.39(1H, dd, J=8.6, 2.6 Hz)

Example 329 Synthesis of N-(5-amino-2-methoxyphenylmethyl)phthalimide

Using the compound obtained in Example 117 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 3.36(2H,brs), 3.79(3H,s), 4.85(2H,s), 6.52-6.59(2H,m), 6.70(6H, d, J=2.3 Hz), 7.68-7.76(2H,m), 7.82-7.90(2H,m)

Example 330 Synthesis of N-(2-methoxy-5-(N′-trifluoroacetoxyamino)phenylmethyl)phthalimide

To a solution of the compound (150 mg) obtained in Example 329 and pyridine (0.13 ml) in anhydrous methylene chloride (5 ml), trifluoroacetic anhydride (0.165 ml) was added dropwise at room temperature and stirred at room temperature for 1 h. Water was added to the reaction mixture, which was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was washed with chloroform to give 176 mg of the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 3.86(3H,s), 4.89(2H,s), 6.87(1H, d, J=8.9 Hz), 7.17(1H, d, J=2.3 Hz), 7.66(1H, dd, J=8.9, 2.3 Hz), 7.71-7.74(2H,m), 7.83-7.87(2H,m)

MS(m/z) 378(M⁺)

Example 331 Synthesis of N-(2-hydroxy-5-(N′-trifluoroacetoxyamino)phenylmethyl)phthalimide

Using the compound obtained in Example 330 as a starting material, the same procedure of Example 318 gave the titled compound (yield, 93%).

¹H-NMR(DMSO-d₆) δ: 4.71(2H,s), 6.84(1H, d, J=8.9 Hz), 7.16(1H, d, J=2.3 Hz), 7.52(1H, dd, J=8.9, 2.3 Hz), 7.86-7.97(4H,m), 9.88(1H,s), 10.88(1H,s)

MS(m/z) 364(M⁺)

Example 332 Synthesis of N-(2-benzyloxy-5-(N′-trifluoroacetoxyamino)phenylmethyl)phthalimide

Using the compound obtained in Example 331 as a starting material and also using potassium carbonate and benzyl bromide as a base and a reagent, respectively, the same procedure of Example 319 gave the titled compound (yield, 53%).

¹H-NMR(DMSO-d₆) δ: 4.80(2H,s), 5.19(2H,s), 7.00-7.18(2H,m), 7.27-7.52(5H,m), 7.68(1H, dd, J=8.9, 2.6 Hz), 7.85-7.98(4H,m), 10.99(1H,brs)

MS(m/z) 454(M⁺)

Example 333 Synthesis of N-(5-amino-2-benzyloxyphenylmethyl)amine

Using the compound (684 mg) obtained in Example 332 as a starting material, the same procedure of Example 180 gave N-(3-aminomethyl-4-benzyloxyphenyl)-2,2,2-trifluoroacetamide. To a solution of the resulting amino compound in 6% hydrous methanol (10.6 ml), potassium carbonate (265 mg) was added and heated under reflux for 2 h. The reaction mixture was distilled under reduced pressure and ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure, thereby giving 339 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 3.79(2H,s), 5.02(2H,s), 6.54(1H, dd, J=8.6, 3.0 Hz), 6.65(1H, d, J=3.0 Hz), 6.76(1H, d, J=8.6 Hz), 7.30-7.43(5H,m)

MS(m/z) 228(M⁺)

Example 334 Synthesis of N-(5-amino-2-benzyloxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 333 as a starting material, the same procedure of Example 253 gave the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 4.26(2H, d, J=5.9 Hz), 4,98(1H,brs), 5.01(2H,s), 6.55(1H, dd, J=8.3, 2.6 Hz), 6.67(1H, d, J=2.6 Hz), 6.76(1H, d, J=8.3 Hz), 7.31-7.40(5H,m)

MS(m/z) 328(M⁺)

Example 335 Synthesis of N-(2-benzyloxy-5-thioureidophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 334 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 81%).

¹H-NMR(DMSO-d₆) δ: 1.40(9H,s), 4.17(2H, d, J=5.9 Hz), 5,13(2H,s), 7.00(1H, d, J=8.6 Hz), 7.07(1H, d, J=2.3 Hz), 7.11-7.22(2H,m), 7.26-7.50(4H,m), 9.51(1H,brs)

Example 336 Synthesis of N-(2-benzyloxy-5-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 335 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=7.3 Hz), 1.43(9H,s), 3.00-3.07(2H,m), 4.32(2H, d, J=5.6 Hz), 4.50(1H,brs), 4.97(1H,brs), 5.07(2H,s), 6.72-6.90(3H,m), 7.32-7.42(5H,m)

MS(m/z) 415M³⁰ )

Example 337 Synthesis of N-(2-benzyloxy-5-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 336 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.23(2H, q, J=7.3 Hz), 4.24(2H,s), 5.34(2H,s), 7.24-7.60(8H,m)

Example 338 Synthesis of N-(2-benzyloxy-5-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 334 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 70%).

¹H-MR(CDCl₃) δ: 1.07(3H, t, J=6.9 Hz), 1.44(9H,s), 1.53(9H,s), 3.36-3.41(2H,m), 4.33(2H, d, J=5.6 Hz), 4.98(1H,brs), 5.10(2H,s), 6.92(1H, d, J=8.6 Hz), 7.01-7.19(2H,m), 7.30-7.45(5H,m)

Example 339 Synthesis of N-(2-benzyloxy-5-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 338 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 3.29(2H, q, J=7.3 Hz), 4.22(2H,s), 5.32(2H,s), 7.20-7.58(8H,m)

MS(m/z) 298(M⁺)

Example 340 Synthesis of N-(2-benzyloxy-5-(N′-nitroguanidino)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 334 as a starting material, the same procedure of Example 6 gave the titled compound (yield, 87%).

¹H-NMR (DMSO-d₆) δ: 1.40(9H,s ), 4.19(2H, d, J=4.0 Hz), 5.15(2H,s), 7.02-7.20(4H,m), 7.28-7.51(5H,m), 8.30(1H,s)

Example 341 Synthesis of N-(2-benzyloxy-5-(N′-nitroguanidino)phenylmethyl)amine hydrochloride

Using the compound obtained in Example 340 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 32%).

¹H-NMR(D₂O) δ: 4.22(2H,s), 5.31(2H,s), 7.20-7.24(1H,m), 7.32-7.39(2H,m), 7.40-7.57(5H,m)

Example 342 Synthesis of 2-methoxy-5-nitrophenylacetic acid diphenylmethyl ester

Using 2-methoxyphenylacetic acid (5.00 g) as a starting material, the same procedure of Example 188 gave 2-methoxy-5-nitrophenylacetic acid. To a solution of the resulting nitro compound in methylene chloride (140 ml), a solution of diphenyldiazomethane in methylene chloride was added at room temperature until the reaction mixture turned purple and then acetic acid was added until the purple color of the reaction mixture disappeared. The reaction mixture was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 2.34 g of the titled compound (yield, 21%).

¹H-NMR(CDCl₃) δ: 3.73(3H,s), 3.77(2H,s), 6.88(1H, d, J=8.9 Hz), 6.91(1H,s), 7.20-7.39(10H,m), 8.12(1H, d, J=2.6 Hz), 8.20(1H, dd, J=8.6, 2.6 Hz)

Example 343 Synthesis of 2-(2-methoxy-5-nitrophenyl)propionic acid diphenylmethyl ester

Using the compound obtained in Example 342 as a starting material and also using methyl iodide (1 eq.) as a reagent, the same procedure of Example 1a gave the titled compound (yield, 46%).

¹H-NMR(CDCl₃) δ: 1.55(3H, d, J=7.3 Hz), 3.63(3H,s), 4.08(1H, q, J=7.3 Hz), 6.84(1H, d, J=8.9 Hz), 6.91(1H,s), 7.15-7.38(10H,m), 8.12(1H, d, J=2.6 Hz), 8.19(1H, dd, J=8.9, 2.6 Hz)

Example 344 Synthesis of 2-(2-methoxy-5-nitrophenyl)-2-methyl-propionic acid diphenylmethyl ester

Using the compound obtained in Example 343 as a starting material, the same procedure of Example 343 gave the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.60(6H,s), 3.26(3H,s), 6.73(1H, d, J=8.9 Hz), 6.94(1H,s), 7.12-7.31(10H,m), 8.19(1H, dd, J=8.9, 2.6 Hz), 8.26(1H, d, J=2.6 Hz)

Example 345 Synthesis of 2-(2-methoxy-5-nitrophenyl)-2-methylpropionic acid

Using the compound obtained in Example 344 as a starting material, the same procedure of Example 1b gave the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 1.60(6H,s), 3.92(3H,s), 6.95(1H, d, J=9.2 Hz), 8.18-8.23(2H,m)

MS(m/z) 239(M⁺)

Example 346 Synthesis of N-(1-(2-methoxy-5-nitrophenyl)-1-methyl-ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 345 as a starting material, the same procedure of Example 1c gave the titled compound (yield, 40%).

¹H-NMR(CDCl₃) δ: 1.33(9H,brs), 1.70(6H,s), 3.95(3H,s), 5.06(1H,brs), 6.94(1H, d, J=8.9 Hz), 8.15(1H, dd, J=8.9, 2.6 Hz), 8.26(1H, d, J=2.6 Hz)

Example 347 Synthesis of N-(1-(5-amino-2-methoxyphenyl)-1-methyl-ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 346 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.33(9H,brs), 1.65(6H,s), 3.77(3H,s), 5.21(1H,brs), 6.54(1H, dd, J=8.6, 3.0 Hz), 6.70-6.74(2H,m)

MS(m/z) 280(M⁺)

Example 348 Synthesis of N-(1-(2-methoxy-5-thioureidophenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 347 as a starting material, the same procedure of Example 120 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.66(6H,s), 3.85(3H,s), 5.08(1H,brs), 6.14(2H,brs), 6.90(1H, d, J=8.9 Hz), 7.07(1H, dd, J=8.9, 2.0 Hz), 7.23(1H, d, J=2.0 Hz), 7.80(1H,brs)

MS(m/z) 339(M⁺)

Example 349 Synthesis of N-(1-(5-(S-ethylisothioureido)-2-methoxy-phenyl)-1-methylethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 348 as a starting material, the same procedure of Example 27 gave the titled compound (yield, 70%). 1H-NMR(CDCl₃) δ: 1.34(9H,s), 1.36(3H, t, J=7.6 Hz), 1.66(6H,s), 3.03(2H, q, J=7.6 Hz), 3.81(3H,s), 5.16(1H,brs), 6.80-6.91(3H,m)

MS(m/z) 367(M⁺)

Example 350 Synthesis of N-(1-(5-(S-ethylisothioureido)-2-methoxyphenyl)-1-methylethyl)amine

Using the compound (111 mg) obtained in Example 349 as a starting material, reaction was performed as in Example 5 and the resulting residue was purified by basic silica gel column chromatography (eluent, n-hexane chloroform=1:3) to give 24.9 mg of the titled compound (yield, 42%).

¹H-NMR(CDCl₃) δ: 1.34-1.41(3H,m), 1.51(6H,s), 3.01-3.15(2H,m), 3.85(3H,s), 4.50(1H,brs), 6.69-6.92(3H,m)

MS(m/z) 267(M⁺)

Example 351 Synthesis of N,N′-di-(t-butoxycarbonyl)-N-(3-nitrophenylmethyl)hydrazine

To a solution of triphenylphosphine (2.06 g) in tetrahydrofuran (20 ml), a solution of di-t-butyl azodicarboxylate (1.80 g) in tetrahydrofuran (15 ml) was added dropwise under ice cooling and stirred for 15 min. To the reaction mixture, a solution of m-nitrobenzyl alcohol (1.0 g) in tetrahydrofuran (15 ml) was added dropwise and stirred at room temperature for 63 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 2.25 g of the titled compound (yield, 94%).

¹H-NMR(CDCl3) δ: 1.47(9H,s), 1.49(9H,s), 4.72(2H,s), 6.30(1H,brs), 7.51(1H, t, J=7.3 Hz), 7.65(1H, d, J=7.3 Hz), 8.15(1H, d, J=7.3 Hz), 8.16(1H,s)

Example 352 Synthesis of N-(3-aminophenylmethyl)-N,N′-di-(t-butoxy-carbonyl)hydrazine

Using the compound obtained in Example 351 as a starting material, the same procedure of Example 2 gave 985 mg of the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 1.48(9H,s), 4.56(2H,s), 6.25(1H,brs), 6.59(1H, d, J=6.9 Hz), 6.65(1H, d, J=6.9 Hz), 6.81-6.98(2H,m)

Example 353 Synthesis of N,N′-di-(t-butoxycarbonyl)-N-(3-thioureidophenylmethyl)hydrazine

Using the compound obtained in Example 352 as a starting material, the same procedure of Example 120 gave 173 mg of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.35(9H,s), 1.48(9H,s), 4.60(2H,s), 6.44(1H,brs), 6.57(2H,brs), 7.08-7.21(2H,m), 7.26-7.40(2H,m), 8.27(1H,m)

Example 354 Synthesis of N,N′-di-(t-butoxycarbonyl)-N-(3-(S-ethylisothioureido)phenylmethyl)hydrazine hydroiodide

Using the compound obtained in Example 353 as a starting material, the same procedure of Example 27 gave 143 mg of the titled compound (yield, 79%).

¹H-NMR(CDCl₃) δ: 1.41(3H, t, J=7.3 Hz), 1.44(9H,s), 1.48(9H,s), 3.31(2H, q, J=7.3 Hz), 4.64(2H,s), 6.40(1H,brs), 7.23-7.41(4H,m)

Example 355 Synthesis of 3-(S-ethylisothioureido)phenylmethylhydrazine trihydrochloride

Using the compound obtained in Example 354 as a starting material, the same procedure of Example 5 gave 62 mg of the titled compound (yield, 79%).

¹H-NMR(DMSO-d₆) δ: 1.34(3H, t, J=7.3 Hz), 3.28-3.40(2H,m), 4.08(2H,s), 7.30(1H, d, J=7.6 Hz), 7.41(1H,s), 7.42(1H, d, J=7.6 Hz), 7.53(1H, t, J=7.6 Hz), 9.26(1H,brs), 9.61(1H,brs), 11.51(1H,brs)

MS(m/z) 224(M⁺)

Example 356 Synthesis of N,N′-di-(t-butoxycarbonyl)-N-(3-(N′-nitroguanidino)phenylmethyl)hydrazine

Using the compound obtained in Example 352 as a starting material, the same procedure of Example 6 gave 22 mg of the titled compound (yield, 18%).

¹H-NMR(CDCl₃) δ: 1.32(9H,s), 1.48(9H,s), 4.62(2H,s), 6.48(1H,brs), 7.15-7.25(2H,m), 7.38(1H, t, J=7.3 Hz), 7.49(1H,s) 9.54(1H,brs)

MS(m/z) 224(M⁺−200)

Example 357 Synthesis of 3-(N′-nitroguanidino)phenylmethylhydrazine dihydrochloride

Using the compound obtained in Example 356 as a starting material, the same procedure of Example 5 gave 15 mg of the titled compound (yield, 74%).

¹H-NMR(DMSO-d₆) δ: 3.75(2H,s), 7.08-7.40(6H,m), 8.26(2H,brs)

MS(m/z) 208(M⁺−16)

Example 358 Synthesis of N-(4-nitrophenylpropyl)carbamic acid t-butyl ester

Using 4-(4-nirophenyl)butylic acid as a starting material, the same procedure of Example 1c gave 400 mg of the titled compound (yield, 30%).

¹H-NMR(CDCl₃) δ: 1.44(9H,s), 1.84(2H, quin, J=7.3 Hz), 2.75(2H, t, J=7.3 Hz), 3.10-3.26(2H,m), 4.57(1H,brs), 7.34(2H, d, J=8.8 Hz), 8.15(2H, d, J=8.8 Hz)

MS(m/z) 281(M⁺+1)

Example 359 Synthesis of N-(4-aminophenylpropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 358 as a starting material, the same procedure of Example 2 gave 170 mg of the titled compound (yield, 48%).

¹H-NMR(CDCl₃) δ: 1.45(9H,s), 1.75(2H, quin, J=7.3 Hz), 2.53(2H, t, J=7.3 Hz), 3.04-3.18(2H,m), 3.53(2H,brs), 4.48(1H,brs), 6.62(2H, d, J=8.3 Hz), 6.95(2H, d, J=8.3 Hz)

Example 360 Synthesis of N-(4-(N′-nitroguanidino)phenylpropyl)carbamic acid t-butyl ester

Using the compound obtained in Example 359 as a starting material, the same procedure of Example 6 gave 42 mg of the titled compound (yield, 37%).

¹H-NMR(CDCl₃) δ: 1.42(9H,s), 1.82(2H, quin, J=7.3 Hz), 2.70(2H, t, J=7.3 Hz), 3.16(2H, dt, J=7.3, 7.3 Hz), 4.54(1H,brs), 7.24(2H, d, J=8.3 Hz), 7.31(2H, d, J=8.3 Hz), 9.60(1H,brs)

Example 361 Synthesis of N-(4-(N′-nitroguanidino)phenylpropyl)amine hydrochloride

Using the compound obtained in Example 360 as a starting material, the same procedure of Example 5 gave 35.5 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.94(2H, quin, J=7.5 Hz), 2.67(2H, t, J=7.5 Hz), 2.74-2.86(2H,m), 7.20(2H, d, J=8.6 Hz), 7.26(2H, d, J=8.6 Hz), 8.16(1H, brs), 9.58(1H,s)

MS(m/z) 237(M⁺)

Example 362 Synthesis of N-(3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using m-nitrobenzyl bromide as a starting material, the same procedure of Example 127 gave 11.7 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 4.86(2H,s), 7.49(1H, dd, J=7.9, 7.5 Hz), 7.65(1H, d, J=7.5 Hz), 8.13(1H, d, J=7.9 Hz), 8.19(1H,s)

Example 363 Synthesis of N-(3-aminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 362 as a starting material, the same procedure of Example 2 gave 5.45 g of the titled compound (yield, 41%).

¹H-NMR(CDCl₃) δ: 1.45(18H,s), 3.60(2H,brs), 4.68(2H,s), 6.53-6.58(1H,m), 6.60(1H,s), 6.66(1H, d, J=7.6 Hz), 7.07(1H, dd, J=7.9, 7.6 Hz)

Example 364 Synthesis of N-(3-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 363 as a starting material, the same procedure of Example 120 gave 2.1 g of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.47(18H,s), 4.78(2H,s), 6.12(2H,brs), 7.10-7.42(4H,m), 7.96(1H,brs)

Example 365 Synthesis of N-(3-(S-methylisothioureido)phenylmethyl)iminodicarboxylic acid di-t-butyl ester hydroiodide

Using the compound obtained in Example 364 as a starting material, the same procedure of Example 4 gave 1.81 g of the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 2.46(3H,s), 4.49(1H,brs), 4.75(2H,s), 6.76-6.88(2H,m), 6.95(1H, d, J=7.6 Hz), 7.20-7.28(1H,m)

Example 366 Synthesis of N-(3-(N′-methylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

A mixture of the compound (158 mg) obtained in Example 365, methylamine hydrochloride (31 mg), triethylamine (156 mg) and dimethylformamide (3 ml) was heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride:methanol=20:1) to give 60 mg of the titled compound (yield, 72%).

¹H-NMR(CDCl₃) δ: 1.45(18H,s), 2.85(3H,s), 4.73(2H,s), 6.81(1H, d, J=7.9 Hz), 6.85(1H,s), 6.89(1H, d, J=7.6 Hz), 7.21(1H, dd, J=7.9, 7.6 Hz)

Example 367 Synthesis of N-(3-(N′-methylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 366 as a starting material, the same procedure of Example 5 gave 49 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 2.84(3H, d, J=4.3 Hz), 4.03(2H,s), 7.22(1H, d, J=7.3 Hz), 7.44-7.51(1H,m), 7.69-7.86(2H,m), 9.82(1H,brs)

MS(m/z) 178(M⁺)

Example 368 Synthesis of N-(3-(N′-ethylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 365 as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 366 gave 59 mg of the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.19(3H, t, J=7.3 Hz), 1.45(18H,s), 3.23(2H, q, J=7.3 Hz), 4.73(2H,s), 6.80(1H, d, J=7.9 Hz), 6.85(1H,s), 6.88(1H, d, J=7.5 Hz), 7.21(1H, dd, J=7.9, 7.5 Hz)

Example 369 Synthesis of N-(3-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 368 as a starting material, the same procedure of Example 5 gave 28.6 mg of the titled compound (yield, 71%).

¹H-NMR(DMSO-d₆) δ: 1.16(3H, t, J=6.9 Hz), 3.26-3.38(2H,m), 4.03(2H, d, J=5.6 Hz), 7.21(1H, d, J=7.6 Hz), 7.36(1H, d, J=7.9 Hz), 7.39(1H,s), 7.48(1H, dd, J=7.9, 7.6 Hz), 7.77(1H,brs), 7.96-8.02(1H,m), 8.47(2H,brs), 9.92(1H,brs)

MS(m/z) 192(M⁺)

Example 370 Synthesis of N-(3-(N′-n-propylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 365 as a starting material and also using n-propylamine as a reagent, the same procedure of Example 366 gave 15 mg of the titled compound (yield, 64%).

¹H-NMR(CDCl₃) δ: 0.96(3H, t, J=7.6 Hz), 1.45(18H,s), 1.54-1.66(2H,m), 3.15(2H, t, J=7.3 Hz), 4.73(2H,s), 6.84-6.97(3H,m), 7.21(1H, d, J=7.9 Hz)

Example 371 Synthesis of N-(3-(N′-n-propylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 370 as a starting material, the same procedure of Example 5 gave 10.7 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 0.92(3H, t, J=7.3 Hz), 1.50-1.62(2H,m), 3.20(2H, dt, J=6.6, 6.3 Hz), 4.04(2H, d, J=5.6 Hz), 7.23(1H, d, J=7.9 Hz), 7.34(1H,s), 7.35(1H, d, J=7.6 Hz), 7.48(1H, dd, J=7.9, 7.6 Hz), 7.67-7.73(1H,m), 7.90-7.96(1H,m), 9.73(1H,brs)

MS(m/z) 206(M⁺)

Example 372 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)dimethylamine

To a solution of the compound (43.5 mg) obtained in Example 40 in acetonitrile (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4N, 0.1 ml) and ethyl iodide (50 mg) were added and heated under reflux for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride methanol=5:1) to give 9.2 mg of the titled compound (yield, 19%).

¹H-NMR(CDCl₃) δ: 1.23(3H, t, J=7.3 Hz), 2.14(6H,s), 2.89(2H, q, J=7.3 Hz), 3.31(2H,s), 6.16(2H,brs), 6.60-6.64(2H,m), 6,84(1H, d, J=7.3 Hz), 7.16(1H, dd, J=7.6, 7.3 Hz)

Example 373 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)dimethylamine

Using the compound obtained in Example 38 as a starting material, the same procedure of Example 233 gave 104 mg of the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.05-1.10(3H,m), 1.51(9H,s), 2.25(6H,s), 3.39-3.42(4H,m), 7.16-7.33(4H,m)

MS(m/z) 320(M⁺)

Example 374 Synthesis of N-(3-(N′-ethylguanidino)phenylmethyl)dimethylamine dihydrochloride

Using the compound obtained in Example 373 as a starting material, the same procedure of Example 5 gave 48.2 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.15(3H, t, J=6.8 Hz), 2.70(3H, d, J=5.0 Hz), 3.29(2H, q, J=6.8 Hz), 4.27(2H, d, J=4.9 Hz), 7.28(1H, d, J=7.6 Hz), 7.42-7.56(2H,m), 7.80(1H,brs), 8.00-8.08(1H,m), 9.92(1H,s), 10.92(1H,brs)

MS(m/z) 220(M⁺)

Example 375 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 44 as a starting material, the same procedure of Example 233 gave 107 mg of the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.06-1.18(3H,m), 1.48(18H,s), 2.83(3H,s), 3.38(2H, q, J=7.0 Hz), 4.42(2H,s), 7.06-7.34(4H,m), 10.58(1H,brs)

Example 376 Synthesis of N-(3-(N′-ethylguanidino)phenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 375 as a starting material, the same procedure of Example 5 gave 57.6 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.16(3H, t, J=6.9 Hz), 2.55(3H, t, J=5.3 Hz), 3.25-3.35(2H,m), 4.12(2H, t, J=5.3 Hz), 7.25(1H, d, J=7.9 Hz), 7.40(1H, d, J=7.9 Hz), 7.41(1H,brs), 7.49(1H, t, J=7.9 Hz), 7.75(1H,brs), 7.94(1H, t, J=5.3 Hz), 9.22(1H,brs), 9.78(1H,brs)

MS(m/z) 206(M⁺)

Example 377 Synthesis of N-(3-nitrophenylmethyl)benzylmethylamine

To a solution of the compound (630 mg) obtained in Example 42 and triethylamine (768 mg) in acetonitrile (20 ml), benzyl bromide (778 mg) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 h and, after addition of water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 925 mg of the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 2.21(3H,s), 3.57(2H,s), 3.60(2H,s), 7.26-7.40(5H,m) 7.48(1H, dd, J=8.3, 7.6 Hz), 7.70(1H, d, J=7.6 Hz), 8.10(1H, d, J=8.3 Hz), 8.24(1H,s)

Example 378 Synthesis of N-(3-aminophenylmethyl)benzylmethylamine

Using the compound obtained in Example 377 as a starting material and also using 5% palladium-carbon and ethyl acetate as a catalyst and a solvent, respectively, reaction was performed as in Example 2 to give 487 mg of the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 2.18(3H,s), 3.43(2H,s), 3.51(2H,s), 3.64(2H,brs), 6.58(1H, d, J=8.6 Hz), 6.73(s,1H), 6.75(1H, d, J=7.6 Hz), 7.10(1H, dd, J=8.6, 7.6 Hz), 7.21-7.39(5H,m)

Example 379 Synthesis of N-(3-thioureidophenylmethyl)benzylmethylamine

Using the compound obtained in Example 378 as a starting material, the same procedure of Example 40 gave 153 mg of the titled compound (yield, 32%).

¹H-NMR (CDCl₃) δ: 2.19(3H,s), 3.54(4H,s), 6.15(2H,brs), 6.60(s, 1H), 6.75-6.79(1H,m), 7.10-7.20(1H,m), 7.26-7.36(6H,m), 8.01-8.18(1H,brs)

Example 380 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)benzylmethylamine dihydrochloride

Using the compound obtained in Example 379 as a starting material, the same procedure of Example 372 gave N-(3-(S-ethylisothioureido)phenylmethyl)benzylmethylamine. To this compound, a solution of hydrogen chloride in 1,4-dioxane (4 N, 0.1 ml) was added and the mixture was concentrated under reduced pressure to give 9.3 mg of the titled compound (yield, 6%).

¹H-NMR(DMSO-d₆) δ: 1.34(3H, t, J=7.3 Hz), 2.54(3H, d, J=3.6 Hz), 3.30-3.40(2H,m), 4.20-4.31(2H,m), 4.38-4.49(2H,m), 7.40-7.50(4H,m), 7.55-7.68(5H,m), 9.43(1H,brs), 9.72(1H,brs), 11.24(1H,brs), 11.66(1H,brs)

Example 381 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)benzylmethylamine

Using the compound obtained in Example 378 as a starting material, the same procedure of Example 233 gave 96 mg of the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 1.01-1.18(3H,m), 1.52(9H,s), 2.18(3H,s), 3.36-3.41(2H,m), 3.49(2H,s), 3.54(2H,s), 4.71(1H,brs), 7.08(1H,brs), 7.26-7.35(9H,m), 10.70(1H,brs)

Example 382 Synthesis of N-(3-(N′-ethylguanidino)phenylmethyl)benzylmethylamine dihydrochloride

Using the compound obtained in Example 381 as a starting material, the same procedure of Example 5 gave 133 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.16(3H, t, J=6.9 Hz), 2.56(3H,s), 3.27-3.33(2H,m), 4.17-4.27(2H,m), 4.36-4.47(2H,m), 7.29(1H, d, J=6.9 Hz), 7.48-7.60(8H,m), 7.73-7.80(1H,m), 7.93-7.99(2H,m), 9.75(1H,brs), 10.87(1H,brs)

MS(m/z) 296(M⁺)

Example 383 Synthesis of N-(3-nitrophenylmethyl)ethylamine

Using m-nitrobenzaldehyde as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 42 gave 2.8 g of the titled compound (yield, 47%).

¹H-NMR(CDCl₃) δ: 1.15(3H, t, J=7.3 Hz), 2.69(2H, q, J=7.3 Hz), 3.91(2H,s), 7.49(1H, dd, J=7.9, 7.6 Hz), 7.68(1H, d, J=7.6 Hz), 8.11(1H, d, J=7.9 Hz), 8.21(1H,s)

Example 384 Synthesis of N-(3-nitrophenylmethyl)ethylcarbamic acid t-butyl ester

Using the compound obtained in Example 383 as a starting material, the same procedure of Example 22 gave 1.94 g of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.11(3H, t, J=7.3 Hz), 1.48(9H,s), 3.20-3.40(2H,m), 4.50(2H,s), 7.50(1H, t, J=8.3 Hz), 7.55-7.60(1H,m), 8.11(1H,s), 8.12(1H, d, J=7.6 Hz)

Example 385 Synthesis of N-(3-aminophenylmethyl)ethylcarbamic acid t-butyl ester

Using the compound obtained in Example 384 as a starting material, the same procedure of Example 2 gave 890 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=6.9 Hz), 1.47(9H,s), 3.13-3.26(2H,m), 3.64(2H,s), 4.34(2H,s), 6.55-6.65(3H,m), 7.09(1H, t, J=7.9 Hz)

Example 386 Synthesis of N-(3-thioureidophenylmethyl)ethylcarbamic acid t-butyl ester

Using the compound obtained in Example 385 as a starting material, the same procedure of Example 120 gave 460 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 1.09(3H, t, J=6.9 Hz), 1.47(9H,s), 3.22-3.30(2H,m), 4.42(2H,s), 6.09(2H,brs), 7.11(1H,s), 7.12(1H, d, J=5.9 Hz), 7.19(1H, d, J=7.6 Hz), 7.39(1H, dd, J=7.6, 5.9 Hz), 7.92(1H,brs)

Example 387 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)ethylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 386 as a starting material, the same procedure of Example 27 gave 155 mg of the titled compound (yield, 49%).

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=6.9 Hz), 1.36(3H, t, J=7.3 Hz), 1.47(9H,s), 2.97-3.12(2H,m), 3.12-3.37(2H,m), 4.39(2H,s), 4.48(1H,brs), 6.75-6.86(2H,m), 6.90(1H, d, J=7.3 Hz), 7.25(1H, dd, J=7.9, 7.3 Hz)

Example 388 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)ethylamine dihydrochloride

Using the compound obtained in Example 387 as a starting material, the same procedure of Example 5 gave 162 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.26(3H, t, J=6.9 Hz), 1.33(3H, t, J=7.3 Hz), 2.90-3.01(2H,m), 3.35(2H, q, J=7.3 Hz), 4.11(2H,s), 7.35(1H, d, J=6.9 Hz), 7.50-7.66(3H,m), 9.53(2H,brs), 9.75(1H,brs), 11.79(1H,brs)

MS(m/z) 237(M⁺)

Example 389 Synthesis of N-(2-methoxy-5-nitrophenylmethyl)methylcarbamic acid t-butyl ester

To methylamine (as 40% MeOH solution, 50 ml), 5-nitro-2-benzyl bromide (1.04 g) was added under ice cooling and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was worked up as in Example 22 to give the titled compound (yield, 39%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 2.92(3H,s), 3.95(3H,s), 4.44(2H,s), 6.92(1H, d, J=9.2 Hz), 7.90-8.19(2H,m)

Example 390 Synthesis of N-(5-amino-2-methoxyphenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 389 as a starting material, the same procedure of Example 2 gave 436 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 2.84(3H,s), 3.41(2H,s), 3.75(3H,s), 4.39(2H,s), 6.47-6.53(1H,m), 6.56(1H, dd, J=8.6, 2.3 Hz), 6.70(1H, d, J=8.6 Hz)

Example 391 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-methoxyphenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 390 as a starting material, the same procedure of Example 233 gave 75 mg of the titled compound (yield, 65%).

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=7.3 Hz), 1.47(9H,s), 1.54(9H,s), 2.87(3H,s), 3.38(2H, quin, J=7.3 Hz), 3.84(3H,s), 4.42(2H,s), 6.86(1H, d, J=8.6 Hz), 6.97(1H,s), 7.02-7.13(1H,m), 10.47(1H,brs)

Example 392 Synthesis of N-(5-(N′-ethylguanidino)-2-methoxyphenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 391 as a starting material, the same procedure of Example 5 gave 42.6 mg of the titled compound (yield, 91%).

¹H-NMR(DMSO-d₆) δ: 1.15(3H, t, J=6.9 Hz), 2.52-2.58(3H,m), 3.20-3.38(2H,m), 3.87(3H,s), 4.05-4.17(2H,m), 7.15(1H, d, J=8.3 Hz), 7.27(1H, d, J=8.9 Hz), 7.36(1H,s), 7.42-7.61(1H,m), 7.66-7.81(1H,m), 9.05(1H,brs), 9.60(1H,brs)

MS(m/z) 236(M⁺)

Example 393 Synthesis of N-(2-methoxy-5-thioureidophenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 390 as a starting material, the same procedure of Example 120 gave 223 mg of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 2.89(3H,s), 3.85(3H,s), 4.41(2H,s), 5.98(2H,brs), 6.88(1H, d, J=8.6 Hz), 7.01(1H,s), 7.05-7.15(1H,m), 7.71(1H,s)

Example 394 Synthesis of N-(5-(S-ethylisothioureido)-2-methoxyphenylmethyl)methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 393 as a starting material, the same procedure of Example 27 gave 217 mg of the titled compound (yield, 66%).

¹H-NMR(CDCl₃) δ: 1.35(3H, t, J=7.3 Hz), 1.45(9H,s), 2.84(3H,s), 2.92-3.10(2H,m), 3.79(3H,s), 4.41(2H,s), 6.73-6.81(3H,m)

Example 395 Synthesis of N-(5-(S-ethylisothioureido)-2-methoxyphenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 394 as a starting material, the same procedure of Example 5 gave 207.8 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.33(3H, t, J=7.3 Hz), 2.52-2.59(3H,m), 3.22-3.36(2H,m), 3.89(3H,s), 4.03-4.18(2H,m), 7.20(1H, d, J=8.6 Hz), 7.37(1H, d, J=8.6 Hz), 7.47(1H,s), 9.08(2H,brs), 9.57(1H,brs), 11.45(1H,brs)

MS(m/z) 253(M⁺)

Example 396 Synthesis of N-(2-methoxy-5-nitrophenylmethyl)dimethylamine

Using 5-nitro-2-benzyl bromide as a starting material, the same procedure of Example 37 gave 3.4 g of the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 2.29(6H,s), 3.47(2H,s), 3.94(3H,s), 6.92(1H, d, J=8.9 Hz), 8.17(1H, dd, J=8.9, 3.0 Hz), 8.23(1H, d, J=3.0 Hz)

Example 397 Synthesis of N-(5-amino-2-methoxyphenylmethyl)dimethylamine

Using the compound obtained in Example 396 as a starting material, the same procedure of Example 2 gave 1.05 g of the titled compound (yield, 37%).

¹H-NMR(CDCl₃) δ: 2.26(6H,s), 3.39(4H,s), 3.76(3H,s), 6.58(1H, dd, J=8.6, 3.0 Hz), 6.71(1H, d, J=8.6 Hz), 6.72(1H, d, J=3.0 Hz)

Example 398 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-methoxyphenylmethyl)dimethylamine

Using the compound obtained in Example 397 as a starting material, the same procedure of Example 233 gave 44 mg of the titled compound (yield, 45%).

¹H-NMR(CDCl₃) δ: 1.02-1.15(3H,m), 1.53(9H,s), 2.35(6H,s), 3.39-3.48(2H,m), 3.49(2H,s), 3.85(3H,s), 6.87(1H, d, J=8.3 Hz), 7.05-7.26(2H,s)

Example 399 Synthesis of N-(5-(N′-ethylguanidino)-2-methoxyphenylmethyl)dimethylamine dihydrochloride

Using the compound obtained in Example 398 as a starting material, the same procedure of Example 5 gave 44 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.15(3H, t, J=6.9 Hz), 2.73(6H, d, J=5.0 Hz), 3.29(2H, quin, J=6.9 Hz), 3.88(3H,s), 4.25(2H, d, J=5.0 Hz), 7.18(1H, d, J=8.9 Hz), 7.31(1H, dd, J=8.9, 1.9 Hz), 7.44(1H, d, J=1.9 Hz), 7.60(1H,brs), 7.78-7.88(1H,m), 9.65(1H,brs), 10.41(1H,brs)

MS(m/z) 250(M⁺)

Example 400 Synthesis of N-(2-methoxy-5-thioureidophenylmethyl)dimethylamine

Using the compound obtained in Example 397 as a starting material, the same procedure of Example 40 gave 410 mg of the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 2.26(6H,s), 3.43(2H,s), 3.85(3H,s), 6.00(2H,brs), 6.88(1H, d, J=8.6 Hz), 7.17(1H, dd, J=8.6, 2.6 Hz), 7.23(1H, d, J=2.6 Hz), 7.77(1H,brs)

Example 401 Synthesis of N-(5-(S-ethylisothioureido)-2-methoxyphenylmethyl)dimethylamine dihydrochloride

Using the compound obtained in Example 400 as a starting material, the same procedure of Example 380 gave 69.5 mg of the titled compound (yield, 98%).

¹H-NMR(DMSO-d₆) δ: 1.33(3H, t, J=7.3 Hz), 2.73(6H, d, J=5.0 Hz), 3.28-3.42(2H,m), 3.89(3H,s), 4.26(2H, d, J=5.0 Hz), 7.24(1H, d, J=8.6 Hz), 7.38-7.44(1H,m), 7.57-7.60(1H,m), 9.27(1H,brs), 9.65(1H,brs), 10.61(1H,brs), 11.58(1H,brs)

MS(m/z) 267(M⁺)

Example 402 Synthesis of N-(3-nitrophenylmethyl)benzylamine

To a solution of m-nitrobenzyl bromide (1.0 g) and diisopropylethylamine (1.19 g) in methanol (50 ml), benzyl bromide (495 mg) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3 days and, after addition of water, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1) to give 555 mg of the titled compound (yield, 50%).

¹H-NMR(CDCl₃) δ: 3.83(2H,s), 3.91(2H,s), 7.23-7.38(5H,m), 7.49(1H, t, J=7.9 Hz), 7.70(1H, d, J=7.9 Hz), 8.07-8.14(1H,m), 8.21(1H,s)

Example 403 Synthesis of N-(3-aminophenylmethyl)benzylcarbamic acid t-butyl ester

Using the compound obtained in Example 402 as a starting material, treatment was performed as in Example 22 and the resulting compound was subsequently subjected to the same reaction as in Example 2 to give 517 mg of the titled compound (yield, 73%).

¹H-NMR(CDCl₃) δ: 1.49(9H,s), 3.65(2H,brs), 4.25-4.43(4H,m), 6.50-6.63(3H,m), 7.11(1H, t, J=7.9 Hz), 7.20-7.40(5H,m)

Example 404 Synthesis of N-(3-thioureidophenylmethyl)benzylcarbamic acid t-butyl ester

Using the compound obtained in Example 403 as a starting material, the same procedure of Example 120 gave 223 mg of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.49(9H,s), 4.41(4H,brs), 6.16(2H,brs), 7.02-7.23(5H,m), 7.26-7.41(4H,m), 8.29(1H,brs)

Example 405 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)benzylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 404 as a starting material, the same procedure of Example 27 gave 205 mg of the titled compound (yield, 66%).

¹H-NMR(CDCl₃) δ: 1.37(3H, t, J=6.9 Hz), 1.49(9H,s), 3.00-3.12(2H,m), 4.25-4.48(4H,m), 6.75-6.90(2H,m), 7.18-7.38(7H,m)

Example 406 Synthesis of N-(3-(S-ethylisothioureido)phenylmethyl)benzylamine dihydrochloride

Using the compound obtained in Example 405 as a starting material, the same procedure of Example 5 gave 176 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.35(3H, t, J=6.9 Hz), 3.30-3.42(2H,m), 4.17-4.26(4H,m), 7.38-7.65(9H,m), 9.46(1H,brs), 9.78(1H,brs), 10.02(1H,brs), 11.80(1H,brs)

MS(m/z) 299(M⁺)

Example 407 Synthesis of N-(2-methyl-3-nitrophenylmethyl)methylcarbamic acid t-butyl ester

Using 2-methyl-3-nitrobenzyl bromide as a starting material, the same procedure of Example 389 gave 900 mg of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 2.38(3H,s), 2.83(3H,s), 4.51(2H,s), 7.30-7.34(2H,m), 7.65-7.69(1H,m)

Example 408 Synthesis of N-(3-amino-2-methylphenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 407 as a starting material, the same procedure of Example 2 gave 805 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.48(9H,s), 2.08(3H,s), 2.73(3H,s), 3.62(2H,brs), 4.44(2H,s), 6.59(1H, d, J=7.6 Hz), 6.64(1H, d, J=7.6 Hz), 6.99(1H, t, J=7.6 Hz)

Example 409 Synthesis of N-(2-methyl-3-thioureidophenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 408 as a starting material, the same procedure of Example 120 gave 225 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.47(9H,s), 2.23(3H,s), 2.84(3H,s), 4.46(2H,s), 5.79(2H,brs), 7.17(1H, dd, J=6.9, 6.6 Hz), 7.23-7.32(2H,m), 7.56(1H,brs)

Example 410 Synthesis of N-(3-(S-ethylisothioureido)-2-methylphenylmethyl)methylcarbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 409 as a starting material, the same procedure of Example 27 gave 114 mg of the titled compound (yield, 76%).

¹H-NMR(CDCl₃) δ: 1.39(3H, t, J=7.6 Hz), 1.47(9H,s), 2.07(3H,s), 2.78(3H,s), 3.02-3.18(2H,m), 4.35(1H,brs), 4.45(2H,s), 6.75(1H, d, J=7.3 Hz), 6.82(1H, d, J=7.6 Hz), 7.11(1H, dd, J=7.6, 7.3 Hz)

Example 411 Synthesis of N-(3-(S-ethylisothioureido)-2-methylphenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 410 as a starting material, the same procedure of Example 5 gave 128 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.34(3H, t, J=6.9 Hz), 2.27(3H,s), 2.60-2.65(3H,m), 3.25-3.35(2H,m), 4.20-4.27(2H,m), 7.31(1H, d, J=7.6 Hz), 7.41(1H, dd, J=7.6, 7.3 Hz), 7.60(1H, d, J=7.3 Hz), 9.23(2H,brs), 9.45-9.60(1H,m), 11.46(1H,brs)

MS(m/z) 238(M⁺+1)

Example 412 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)2-methylphenylmethyl)methylcarbamic acid t-butyl ester

Using the compound obtained in Example 408 as a starting material, the same procedure of Example 233 gave 43 mg of the titled compound (yield, 53%).

¹H-NMR(CDCl₃) δ: 1.01-1.18(3H,m), 1.48(9H,s), 1.54(9H,s), 2.18(3H,s), 2.81(3H,s), 3.38-3.42(2H,m), 4.45(1H,s), 7.05-7.26(3H,m), 10.56(1H,brs)

Example 413 Synthesis of N-(3-(N′-ethylguanidino)-2-methylphenylmethyl)methylamine dihydrochloride

Using the compound obtained in Example 412 as a starting material, the same procedure of Example 5 gave 30.5 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.15(3H, t, J=7.3 Hz), 2.28(3H,s), 2.63(3H, t, J=5.0 Hz), 3.22-3.35(2H,m), 4.19(2H, t, J=5.6 Hz), 7.26(1H, d, J=7.6 Hz), 7.35(1H, dd, J=7.6, 7.3 Hz), 7.45(1H,brs), 7.52(1H, d, J=7.3 Hz), 7.61-7.72(1H,m), 9.21(2H,brs), 9.55(1H,brs)

MS(m/z) 220(M⁺)

Example 414 Synthesis of N-(2-methyl-3-thioureidophenylmethyl)dimethylamine

Using N-(3-amino-2-methylphenylmethyl)dimethylamine as a starting material, the same procedure of Example 40 gave 355 mg of the titled compound (yield, 56%).

¹H-NMR(CDCl₃) δ: 2.25(6H,s), 2.32(3H,s), 3.40(2H,s), 5.81(2H,brs), 7.14-7.32(3H,m), 7.53-7.72(1H,m)

Example 415 Synthesis of N-(3-(S-ethylisothioureido)-2-methylphenyl-methyl)dimethylamine dihydrochloride

Using the compound obtained in Example 414 as a starting material, the same procedure of Example 380 gave 108 mg of the titled compound (yield, 83%).

¹H-NMR(DMSO-d₆) δ: 1.34(3H, t, J=7.3 Hz), 2.31(3H,s), 2.77(6H, d, J=4.0 Hz), 3.28-3.40(2H,m), 4.40(2H, d, J=5.3 Hz), 7.35-7.46(2H,m), 7.72(1H, d, J=6.9 Hz), 9.56(1H, brs), 10.66(1H,brs), 11.49(1H,brs)

MS(m/z) 252(M⁺+1)

Example 416 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)2-methylphenylmethyl)dimethylamine

Using N-(3-amino-2-methylphenylmethyl)dimethylamine as a starting material, the same procedure of Example 233 gave 46 mg of the titled compound (yield, 45%).

¹H-NMR(CDCl₃) δ: 1.00-1.08(3H,m), 1.52(9H,s), 2.26(9H,s), 3.33-3.43(2H,m), 3.42(2H,s), 4.30(1H,brs), 7.02-7.20(3H,m), 10.57(1H,brs)

Example 417 Synthesis of N-(3-(N′-ethylguanidino)-2-methylphenylmethyl)dimethylamine dihydrochloride

Using the compound obtained in Example 416 as a starting material, the same procedure of Example 5 gave 37.3 mg of the titled compound (yield, 92%).

¹H-NMR(DMSO-d₆) δ: 1.15(3H, t, J=7.3 Hz), 2.32(3H,s), 2.77(6H, d, J=4.0 Hz), 3.23-3.35(2H,m), 4.38(2H, d, J=5.3 Hz), 7.29(1H, d, J=7.6 Hz), 7.37(1H, dd, J=7.9, 7.6 Hz), 7.53(1H,brs), 7.64(1H, d, J=7.9 Hz), 7.70-7.86(1H,m), 9.67(1H,brs), 10.71(1H,brs)

MS(m/z) 235(M⁺+1)

Example 418 Synthesis of 2-methoxy-3-nitrobenzyl alcohol

A mixture of 2-methoxy-3-nitrobenzoic acid methyl ester (4.82 g), lithium borohydride (298 mg), trimethyl borate (0.27 ml) and anhydrous tetrahydrofuran (200 ml) was heated under reflux for 5 h. The reaction mixture was distilled under reduced pressure and ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=1:1) to give 3.18 g of the titled compound (yield, 76%).

¹H-NMR(CDCl₃) δ: 2.08(1H, t, J=5.6 Hz), 3.94(3H,s), 4.81(2H, d, J=5.6 Hz), 7.23(1H, t, J=7.9 Hz), 7.69(4H, d, J=7.9 Hz), 7.79(4H, d, J=7.9 Hz)

Example 419 Synthesis of 2-methoxy-3-nitrobenzyl bromide

Using the compound obtained in Example 418 as a starting material, the same procedure of Example 55 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 2.03(3H,s) 4.57(2H,s), 7.21(3H, t, J=7.9 Hz), 7.65(1H, dd, J=7.9, 1.6 Hz), 7.81(1H, dd, J=7.9, 1.6 Hz)

Example 420 Synthesis of N-(2-methoxy-3-nitrohenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 419 as a starting material, the same procedure of Example 127 gave the titled compound (yield, 64%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 3.92(3H,s), 4.91(2H,s), 7.19(1H, t, J=7.9 Hz), 7.41(1H, d, J=7.9 Hz), 7.74(1H, d, J=7.9 Hz)

Example 421 Synthesis of N-(3-amino-2-methoxyphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 420 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.44(18H,s), 3.75(3H,s), 4.85(2H,s), 6.54(1H, d, J=7.3 Hz), 6.64(1H, d, J=7.3 Hz), 6.87(1H, t, J=7.3 Hz)

Example 422 Synthesis of N-(2-methoxy-3-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 421 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 3.83(3H,s), 4.86(2H,s), 6.29(2H,brs), 7.11-7.20(3H,m), 7.88(1H,brs)

Example 423 Synthesis of N-(3-(S-ethylisothioureido)-2-methoxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 422 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 86%).

¹H-NMR(CDCl₃) δ: 1.39(3H, t, J=6.9 Hz), 1.45(9H,s), 3.08-3.18(2H,m), 3.77(3H,s), 4.31-4.32(2H,m), 4.54(2H,brs), 4.98(1H,brs), 6.80-7.01(3H,m)

Example 424 Synthesis of N-(3-(S-ethylisothioureido)-2-methoxyphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 423 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 88%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.3 Hz), 3.27(2H, q, J=7.3 Hz), 3.87(3H,s), 4.28(2H,s), 7.35(1H, t, J=7.9 Hz), 7.45(1H, dd, J=7.9, 2.0 Hz), 7.54(1H, dd, J=7.9, 2.0 Hz)

Example 425 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylquanidino)-2-methoxyphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 421 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 50%).

¹H-NMR(CDCl₃) δ: 1.45(27H,s), 1.48-1.58(3H,m), 3.38-3.48(2H,m), 3.78(3H,s), 4.86(2H,s), 7.00-7.25(3H,m)

Example 426 Synthesis of N-(3-(N′-ethylguanidino)-2-methoxyphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 425 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 93%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 3.34(2H, q, J=7.3 Hz), 3.87(3H,s), 4.25(2H,s), 7.29(1H, t, J=7.6 Hz), 7.39-7.49(2H,m)

Example 427 Synthesis of N-(3-methyl-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using 3-methyl-5-nitrobenzyl bromide as a starting material, the same procedure of Example 127 gave the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.49(18H,s), 2.44(3H,s), 4.82(2H,s), 7.44(1H,s), 7.94(1H,s), 7.98(1H,s)

Example 428 Synthesis of N-(5-amino-3-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 427 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 2.23(3H,s), 3.56(2H,brs), 4.65(2H,s), 6.39(1H,s), 6.41(1H,s), 6.49(1H,s)

Example 429 Synthesis of N-(3-methyl-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 428 as a starting material, the same procedure of Example 120 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 2.34(3H,s), 4.74(2H,s), 6.10(2H,brs), 6.91(1H,s), 6.96(1H,s), 7.06(1H,s), 7.84(1H,brs)

Example 430 Synthesis of N-(5-(S-ethylisothioureido)-3-methylphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 429 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=7.3 Hz), 1.46(9H,s), 2.30(3H,s), 2.95-3.10(2H,m), 4.24(2H, d, J=5.6 Hz), 4.49(1H,brs), 4.80(1H,brs), 6.64(2H,s), 6.76(1H,s)

Example 431 Synthesis of N-(5-(S-ethylisothioureido)-3-methylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 430 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 70%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 2.40(3H,s), 3.23(2H, q, J=7.3 Hz), 4.20(2H,s), 7.23(1H,s), 7.28(1H,s), 7.37(1H,s)

Example 432 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-3-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 428 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 64%).

¹H-NMR(CDCl₃) b: 1.01-1.15(3H,m), 1.47(27H,s), 2.32(3H,s), 3.34-3.45(2H,m), 4.72(2H,s), 6.82-7.00(3H,m)

Example 433 Synthesis of N-(5-(N′-ethylguanidino)-3-methylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 432 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 80%).

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 2.38(3H,s), 3.32(2H, q, J=7.3 Hz), 4.17(2H,s), 7.15(1H,s), 7.20(1H,s), 7.26(1H,s)

Example 434 Synthesis of N-(2-benzylamino-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using benzylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 4.45-4.48(2H,m), 4.75(2H,s), 6.42-6.55(1H,m), 7.13-7.39(5H,m), 7.97-8.09(1H,m), 8.17-8.23(1H,m)

Example 435 Synthesis of N-(5-amino-2-benzylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 434 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 32%).

¹H-NMR(CDCl₃) δ: 1.44(18H,s), 4.31(2H,s), 4.69(2H,s), 6.43(1H, d, J=8.3 Hz), 6.52(1H, d, J=8.3 Hz), 6.68(1H,s), 7.19-7.40(5H,m)

Example 436 Synthesis of N-(2-benzylamino-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 435 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 32%).

¹H-NMR(CDCl₃) δ: 1.45(18H,s), 4.39(2H, d, J=5.6 Hz), 4.70(2H,s), 5.91(2H,brs), 6.10(1H, t, J=5.6 Hz), 6.50(1H, d,J=8.6 Hz), 6.90-6.94(1H,m), 7.13-7.14(1H,m), 7.25-7.34(5H,m), 7.55(1H,brs)

Example 437 Synthesis of N-(2-benzylamino-5-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 436 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 48%).

¹H-NMR(CDCl₃) δ: 1.34(3H, t, J=7.3 Hz), 1.40(9H,s), 3.00(2H, q, J=7.3 Hz), 4.25(2H, d, J=6.3 Hz), 4.36(2H,s), 4.83(1H,brs), 5.16(1H,brs), 6.50-6.54(1H,m), 6.60-6.75(2H,m), 7.20-7.39(5H,m)

Example 438 Synthesis of N-(2-benzylamino-5-(S-ethylisothioureido)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 437 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 99%).

¹H-NMR(D₂O) δ: 1.40(3H, t, J=7.3 Hz), 3.20(2H, q, J=7.3 Hz), 4.21(2H,s), 4.53(2H,s), 6.88(1H, d, J=8.6 Hz), 7.20(1H, dd, J=8.6, 2.6 Hz), 7.26(1H, d, J=2.6 Hz)

Example 439 Synthesis of N-(2-benzylamino-5-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 435 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 54%).

¹H-NMR(CDCl₃) δ: 1.04(3H, t, J=7.3 Hz), 1.44(18H,s), 1.52(9H,s), 3.30-3.41(2H,m), 4.38(2H, d, J=4.6 Hz), 4.53(1H,brs), 4.69(2H,s), 5.87(1H,brs), 6.51(1H, d, J=8.6 Hz), 6.86-6.94(1H,m), 7.08-7.13(1H,m), 7.32-7.35(5H,m)

Example 440 Synthesis of N-(2-benzylamino-5-(N′-ethylguanidino)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 439 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 89%).

¹H-NMR(D₂O) δ: 1.19(3H, t, J=7.3 Hz), 3.28(2H, q, J=7.3 Hz), 4.16(2H, s), 4.52(2H, s), 6.90(1H, d, J=8.6 Hz), 7.16-7.24(2H, m), 7.32-7.48(5H, m)

Example 441 Synthesis of N-(2-(2-t-butoxycarbonylaminoethyl)phenyl)amidinosulfonic acid

Using the compound obtained in Example 331 as a starting material, the same procedure of Example 277 gave the titled compound (yield, 86%).

¹H-NMR(DMSO-d₆) δ: 1.36(9H, s), 2.64(2H, t, J=6.9 Hz), 3.16(2H, dt, J=5.3, 6.9 Hz), 6.72(1H, t, J=5.3 Hz), 7.12-7.20(1H, m), 7.28-7.40(3H, m), 9.48(1H, brs), 11.29(1H, brs),

Example 442 Synthesis of N-(2-(N′-ethylquanidino)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 441 as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 302 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.22(3H, t, J=7.3 Hz), 1.36(9H, s), 2.75(2H, t, J=6.3 Hz), 3.28-3.37(4H, m), 3.99(2H, brs), 5.89(1H, brs), 6.91-7.03(2H, m), 7.13-7.19(2H, m)

Example 443 Synthesis of N-(2-(N′-ethylguanidino)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 442 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 90%).

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 3.01(2H, t, J=7.6 Hz), 3.19-3.37(4H, m), 7.32-7.50(4H, m)

Example 444 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-fluorophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 314 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.03-1.08(3H, m), 1.47(27H, s), 3.15-3.22(2H, m), 4.83(2H, s),6.99-7.15(3H, m)

Example 445 Synthesis of N-(5-(N′-ethylguanidino)-2-fluorophenylmethyl)amine dihydrochloride

Using the compound obtained in Example 444 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 90%).

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 3.31(2H, q, J=7.3 Hz), 4.27(2H, s), 7.28-7.46(3H, m)

Example 446 Synthesis of N-(2-methylamino-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using methylamine hydrochloride as a reagent, the same procedure of Example 264 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.50(18H, s), 2.92(3H, d, J=4.9 Hz), 4.68(2H, s), 6.50(1H, d, J=9.3 Hz), 6.72(1H, brs), 8.08-8.15(2H, m)

Example 447 Synthesis of N-(5-amino-2-methylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 446 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.46(18H, s), 2.78(3H, s), 3.60(2H, brs), 4.63(2H, s), 6.45-6.68(3H, m),

MS(m/z)351(M⁺)

Example 448 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-methylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 447 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 47%).

¹H-NMR(CDCl₃) δ: 1.05(3H, t, J=7.3 Hz), 1.47-1.53(27H, m), 2.84(3H, s), 3.35-3.39(2H, m), 4.63(2H, s), 5.30(1H, brs), 6.55(1H, d, J=8.6 Hz), 6.99-7.07(2H, m), 10.39(1H, brs)

Example 449 Synthesis of N-(5-(N′-ethylguanidino)-2-methylaminophenylmethyl)amine trihydrochloride

Using the compound obtained in Example 448 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.25(3H, t, J=7.3 Hz), 3.10(3H, s), 3.35(2H, q, J=7.3 Hz), 4.36(2H, s), 7.50-7.51(3H, m)

MS(m/z)221(M⁺)

Example 450 Synthesis of N-(2-methylamino-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 447 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.48(18H, s), 2.84(3H, d, J=3.5 Hz), 4.63(2H, s), 5.50(2H, brs), 6.50(1H, d, J=8.6 Hz), 7.04(1H, dd, J=8.6, 2.7 Hz), 7.12(1H, d, J=2.7 Hz), 7.99(1H, brs)

MS(m/z)410(M⁺)

Example 451 Synthesis of N-(5-(S-ethylisothioureido)-2-methylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 450 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.31(3H, t, J=7.3 Hz), 1.47(18H, s), 2.82(3H, s), 3.01(2H, q, J=7.3 Hz), 4.64(2H, s), 6.55(1H, d, J=7.6 Hz), 6.81-6.88(2H, m)

MS(m/z)438(M⁺)

Example 452 Synthesis of N-(5-(S-ethylisothioureido)-2-methylaminophenylmethyl)amine trihydrochloride

Using the compound obtained in Example 451 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.04(3H, s), 3.25(2H, q, J=7.3 Hz), 4.32(2H, s), 7.40(1H, d, J=8.6 Hz), 7.49-7.55(2H, m)

MS(m/z)238(M⁺)

Example 453 Synthesis of N-(2-ethylamino-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 264 gave the titled compound (yield, 52%).

¹H-NMR(CDCl₃) δ: 1.33(3H, t, J=7.3 Hz), 1.50(18H, s), 3.14-3.34(2H, m), 5.37(2H, s), 6.52(1H, d, J=8.0 Hz), 6.65(1H, brs), 8.05-8.25(2H, m)

MS(m/z)395(M⁺)

Example 454 Synthesis of N-(5-amino-2-ethylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 453 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.25(3H, t, J=7.3 Hz), 1.46(18H, s), 3.07(2H, q, J=7.3 Hz), 3.55(2H, brs), 4.64(2H, s), 6.46-6.67(3H, m)

MS(m/z)365(M⁺)

Example 455 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-ethylaminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 454 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 50%).

¹H-NMR(CDCl₃) δ: 1.30(3H, t, J=7.2 Hz), 1.43-1.53(30H, m), 3.11-3.17(2H, m), 3.34-3.40(2H, m), 4.45(1H, brs), 4.64(2H, s), 5.29(1H, brs), 6.55(1H, d, J=8.5 Hz), 6.98(1H, dd, J=8.5, 2.7 Hz), 7.07(1H, d, J=2.7 Hz)

Example 456 Synthesis of N-(2-ethylamino-5-(N′-ethylguanidino)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 455 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 89%).

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.3 Hz), 1.36(3H, t, J=7.3 Hz), 3.34(2H, q, J=7.3 Hz), 3.48(2H, q, J=7.3 Hz), 4.44(2H, s), 7.50-7.52(3H, m)

MS(m/z)235(M⁺)

Example 457 Synthesis of N-(2-ethylamino-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 454 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 55%).

¹H-NMR(CDCl₃) δ: 1.29(3H, t, J=7.3 Hz), 1.47(18H, s), 3.14(2H, q, J=7.3 Hz), 4.64(2H, s), 5.90(2H, brs), 6.56(1H, d, J=8.6 Hz), 6.98-7.12(2H, m), 7.55(1H, brs),

MS(m/z)424(M⁺)

Example 458 Synthesis of N-(2-ethylamino-5-(S-ethylisothioureido)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 457 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 60%).

¹H-NMR(CDCl₃) δ: 1.28(3H, t, J=7.3 Hz), 1.34(3H, t, J=7.3 Hz), 1.47(18H, s), 3.01(2H, q, J=7.3 Hz), 3.12(2H, q, J=7.3 Hz), 4.66(1H, d, J=8.3 Hz), 6.55(1H, d, J=8.3 Hz), 6.79(1H, dd, J=8.3, 2.4 Hz), 6.86(1H, d, J=2.4 Hz)

MS(m/z)453(M⁺+1)

Example 459 Synthesis of N-(2-ethylamino-5-(S-ethylisothioureido)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 458 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 63%).

¹H-NMR(D₂O) δ: 1.31(3H, t, J=7.3 Hz), 1.41(3H, t, J=7.3 Hz), 3.23(2H, q, J=7.3 Hz), 3.32-3.42(2H, m), 4.28(2H, s), 7.30-7.49(3H, m)

MS(m/z)252(M⁺)

Example 460 Synthesis of N-(2-ethyl-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using 3-chloromethyl-4-ethylnitrobenzene as a starting material, the same procedure of Example 127 gave the titled compound (yield, 72%).

¹H-NMR(CDCl₃) δ: 1.28(3H, t, J=7.4 Hz), 1.49(18H, s), 2.76(2H, q, J=7.4 Hz), 4.88(2H, s), 7.33(1H, d, J=8.3 Hz), 7.99-8.10(2H, m)

Example 461 Synthesis of N-(5-amino-2-ethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 460 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.16(3H, t, J=7.3 Hz), 1.44(18H, s), 2.54(2H, q, J=7.3 Hz), 4.77(2H, brs), 6.45-6.60(2H, m), 6.95(1H, d, J=8.3 Hz)

MS(m/z)350(M⁺)

Example 462 Synthesis of N-(2-ethyl-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 461 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.23(3H, t, J=7.5 Hz), 1.47(18H, s), 2.65(2H, q, J=7.5 Hz), 4.81(2H, s), 6.11(2H, brs), 7.00(1H, d, J=1.8 Hz), 7.04(1H, dd, J=8.0, 1.8 Hz), 7.23(1H, d, J=8.0 Hz) 7.99(1H, brs)

Example 463 Synthesis of N-(5-(S-ethylisothioureido)-2-ethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 462 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 76%).

¹H-NMR(CDCl₃) δ: 1.19(3H, t, J=7.3 Hz), 1.28-1.34(3H, m), 1.43(18H, s), 2.61(2H, q, J=7.3 Hz), 3.00-3.10(2H, m), 4.80(2H, s), 6.67-7.10(3H, m)

MS(m/z)437(M⁺)

Example 464 Synthesis of N-(5-(S-ethylisothioureido)-2-ethylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 463 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 77%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.4 Hz), 1.42(3H, t, J=7.4 Hz), 2.74(2H, q, J=7.4 Hz), 3.25(2H, q, J=7.4 Hz), 4.29(2H, s), 7.34-7.41(2H, m), 7.52(1H, d, J=8.2 Hz),

MS(m/z)237(M⁺)

Example 465 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-ethylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 461 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.08(3H, t, J=7.3 Hz), 1.26(3H, t, J=7.5 Hz), 1.43-1.69(27H, m), 2.66(2H, q, J=7.3 Hz), 3.39(2H, q, J=7.5 Hz), 4.81(2H, s), 6.96-7.27(3H, m), 10.61(1H, brs),

Example 466 Synthesis of N-(2-ethyl-5-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 465 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 89%).

¹H-NMR(D₂O) δ: 1.19-1.25(6H, m), 2.74(2H, q, J=7.5 Hz), 3.10(2H, q, J=7.3 Hz), 4.27(2H, s), 7.29-7.34(2H, m), 7.45(1H, d, J=7.9 Hz),

MS(m/z)221(M++1)

Example 467 Synthesis of N-(2-methyl-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using 3-chloromethyl-4-methylnitrobenzene as a starting material, the same procedure of Example 127 gave the titled compound (yield, 37%).

¹H-NMR(CDCl₃) δ: 1.49(18H, s), 2.42(3H, s), 4.83(2H, s), 7.27-7.32(1H, m), 7.99-8.03(2H, m)

Example 468 Synthesis of N-(5-amino-2-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 467 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.44(18H, s), 2.18(3H, s), 3.51(2H, brs), 4.71(2H, s), 6.47-6.52(2H, m), 6.85(1H, d, J=8.1 Hz)

Example 469 Synthesis of N-(2-methyl-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 468 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.48(18H, s), 2.30(3H, s), 4.75(2H, s), 6.04(2H, brs), 6.95-7.01(2H, m), 7.24(1H, d, J=7.3 Hz), 7.83(1H, brs)

MS(m/z)396(M⁺+1)

Example 470 Synthesis of N-(5-(S-ethylisothioureido)-2-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 469 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 87%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=7.3 Hz), 1.44(18H, s), 2.25(3H, s), 2.95-3.05(2H, m), 4.74(2H, s), 6.63-6.75(2H, m), 7.05(1H, d, J=7.9 Hz)

MS(m/z)424(M⁺+1)

Example 471 Synthesis of N-(5-(S-ethylisothioureido)-2-methylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 470 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 83%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 2.43(3H, 5), 3.25(2H, q, J=7.3 Hz), 4.28(2H, s), 7.31-7.50(3H, m)

MS(m/z)223(M⁺)

Example 472 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 471 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 55%).

¹H-NMR(CDCl₃) δ: 1.07(3H, t, J=7.0 Hz), 1.44-1.53(27H, m), 2.30(3H, s), 3.31-3.45(2H, m), 4.65(1H, brs), 4.75(2H, s), 6.95-7.20(3H, m)

MS(m/z)507(M⁺+1)

Example 473 Synthesis of N-(5-(N′-ethylguanidino)-2-methylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 472 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 85%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.4 Hz), 2.71(3H, s), 3.31(2H, q, J=7.4 Hz), 4.24(2H, s), 7.24-7.29(2H, m), 7.39-7.44(1H, m)

MS(m/z)206(M⁺)

Example 474 Synthesis of N-(3-methoxy-4-methylphenyl)phthalimide

Using 3-methoxy-4-methylaniline as a starting material, the same procedure of Example 248 gave 1.55 g of the titled compound (yield, 14%)

¹H-NMR(CDCl₃) δ: 2.26(3H, s), 3.85(3H, s), 6.82-6.95(2H, m), 7.21-7.30(1H, m), 7.77-7.81(2H, m), 7.94-7.97(2H, m)

Example 475 Synthesis of N-(4-bromomethyl-3-methoxyphenyl)phthalimide

Using the compound obtained in Example 474 as a starting material, the same procedure of Example 249 gave 80 mg of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 3.93(3H, s), 4.58(2H, s), 6.96-7.10(2H, m), 7.42-7.50(1H, m), 7.79-7.82(2H, m), 7.95-7.98(2H, m)

Example 476 Synthesis of N-(4-cyanomethyl-3-methoxyphenyl)phthalimide

Using the compound obtained in Example 475 as a starting material, the same procedure of Example 250 gave 26 mg of the titled compound (yield, 42%).

¹H-NMR(CDCl₃) δ: 3.73(2H, s), 3.90(3H, s), 7.01-7.14(2H, m), 7.48-7.53(1H, m), 7.80-7.83(2H, m), 7.96-7.99(2H, m)

Example 477 Synthesis of 4-cyanomethyl-3-methoxyaniline

Using the compound obtained in Example 476 as a starting material, the same procedure of Example 251 gave 640 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 3.55(2H, s), 3.75(2H, brs), 3.80(3H, s), 6.18-6.35(2H, m), 7.00-7.14(1H, m)

Example 478 Synthesis of 4-(2-aminoethyl)-3-methoxyaniline

Using the compound obtained in Example 477 as a starting material, the same procedure of Example 252 gave 608 mg of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.68(2H, brs), 2.64(2H, t, J=6.9 Hz), 2.84(2H, t, J=6.9 Hz), 3.61(2H, brs), 3.76(3H, s), 6.18-6.26(2H, m), 6.84-6.95(1H, m)

Example 479 Synthesis of N-(2-(4-amino-2-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 478 as a starting material, the same procedure of Example 253 gave 253 mg of the titled compound (yield, 31%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.68(2H, t, J=6.9 Hz), 3.20-3.35(2H, m), 3.62(2H, brs), 3.77(3H, s), 4.63(1H, brs), 6.20-6.25(2H, m), 6.82-6.92(1H, m)

Example 480 Synthesis of N-(2-(2-methoxy-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 479 as a starting material, the same procedure of Example 120 gave 70 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.42(9H, s), 2.79(2H, t, J=6.9 Hz), 3.25-3.40(2H, m), 3.82(3H, s), 4.60(1H, brs), 6.12(2H, brs), 6.71-6.79(2H, m), 7.16-7.18(1H, m), 7.93(1H, s)

Example 481 Synthesis of N-(2-(4-(S-ethylisothioureido)-2-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 480 as a starting material, the same procedure of Example 95 gave 50 mg of the titled compound (yield, 66%).

¹H-NMR(CDCl₃) δ: 1.37(3H, t, J=7.3 Hz), 1.43(9H, s), 2.75(2H, t, J=6.6 Hz), 2.95-3.20(2H, m), 3.20-3.38(2H, m), 3.79(3H, s), 4.54(1H, brs), 4.61(1H, brs), 6.38-6.60(2H, m), 7.00-7.05(1H, m)

Example 482 Synthesis of N-(2-(4-(S-ethylisothioureido)-2-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 481 as a starting material, the same procedure of Example 5 gave 45 mg of the titled compound (yield, 81%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.03(2H, t, J=6.9 Hz), 3.19-3.28(4H, m), 3.88(3H, s), 6.95-7.00(2H, m), 7.36-7.39(1H, m)

Example 483 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 479 as a starting material, the same procedure of Example 233 gave 118 mg of the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 1.19(3H, t, J=7.3 Hz), 1.43(9H, s), 1.52(9H, s), 2.78(2H, t, J=6.6 Hz), 3.32-3.44(4H, m), 3.80(3H, s), 4.62(1H, brs), 6.56-6.90(2H, m), 7.30-7.80(1H, m), 8.02(1H, brs)

Example 484 Synthesis of N-(2-(4-(N′-ethylguanidino)-2-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 483 as a starting material, the same procedure of Example 5 gave 72 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 3.01(2H, t, J=6.9 Hz), 3.22-3.61(4H, m), 3.87(3H, s), 6.89-6.96(2H, m), 7.30-7.33(1H, m)

Example 485 Synthesis of N-(2-methoxy-4-methylphenyl)phthalimide

Using 2-methoxy-4-methylaniline as a starting material, the same procedure of Example 248 gave 4.46 g of the titled compound (yield, 11%).

¹H-NMR(CDCl₃) δ: 2.41(3H, s), 3.77(3H, s), 6.86-6.90(2H, m), 7.11-7.14(1H, m), 7.75-7.78(2H, m), 7.89-7.95(2H, m)

Example 486 Synthesis of N-(4-bromomethyl-2-methoxyphenyl)phthalimide

Using the compound obtained in Example 485 as a starting material, the same procedure of Example 249 gave 4.46 g of the titled compound (yield, 76%).

¹H-NMR(CDCl₃) δ: 3.82(3H, s), 4.52(2H, s), 7.08-7.24(3H, m), 7.76-7.80(2H, m), 7.93-7.96(2H, m)

Example 487 Synthesis of N-(4-cyanomethyl-2-methoxyphenyl)phthalimide

Using the compound obtained in Example 486 as a starting material, the same procedure of Example 250 gave 2.0 g of the titled compound (yield, 50%).

¹H-NMR(CDCl₃) δ: 3.83(5H, s), 7.02-7.29(3H, m), 7.77-7.81(2H, m), 7.93-7.96(2H, m)

Example 488 Synthesis of 4-cyanomethyl-2-methoxyaniline

Using the compound obtained in Example 487 as a starting material, the same procedure of Example 251 gave 844 mg of the titled compound (yield, 77%). ¹H-NMR(CDCl₃) δ: 3.65(2H, s), 3.70-3.95(5H, m), 6.65-6.72(3H, m)

Example 489 Synthesis of 4-(2-aminoethyl)-2-methoxyaniline

Using the compound obtained in Example 488 as a starting material, the same procedure of Example 252 gave 230 mg of the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 1.43(2H, brs), 2.65(2H, t, J=6.9 Hz), 2.92(2H, t, J=6.9 Hz), 3.69(2H, brs), 3.84(3H, s), 6.61-6.72(3H, m)

Example 490 Synthesis of N-(2-(4-amino-3-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 489 as a starting material, the same procedure of Example 253 gave 95 mg of the titled compound (yield, 26%).

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 2.69(2H, t, J=6.9 Hz), 3.28-3.44(2H, m), 3.84(3H, s), 4.54(1H, brs), 6.59-6.72(3H, m)

Example 491 Synthesis of N-(2-(3-methoxy-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 490 as a starting material, the same procedure of Example 120 gave 38 mg of the titled compound (yield, 73%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.80(2H, t, J=7.3 Hz), 3.30-3.44(2H, m), 3.85(3H, s), 4.57(1H, brs), 6.07(2H, brs), 6.80-6.83(2H, m), 7.21-7.24(1H, m), 7.62(1H, brs)

Example 492 Synthesis of N-(2-(4-(S-ethylisothioureido)-3-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 491 as a starting material, the same procedure of Example 95 gave 25 mg of the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 1.38(3H, t, J=7.3 Hz), 1.44(9H, s), 2.75(2H, t, J=6.9 Hz), 2.88-3.14(2H, m), 3.30-3.42(2H, m), 3.82(3H, s), 4.52(1H, brs), 6.72-6.76(2H, m), 7.26(1H, s)

Example 493 Synthesis of N-(2-(4-(S-ethylisothioureido)-3-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 492 as a starting material, the same procedure of Example 5 gave 19 mg of the titled compound (yield, 92%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.05(2H, t, J=7.3 Hz), 3.18-3.34(4H, m), 3.90(3H, s), 7.02(1H, d, J=7.9 Hz), 7.15(1H, s), 7.30(1H, d, J=7.9 Hz)

Example 494 Synthesis of 4-(2-aminoethyl)-2-chloroaniline

Using 2-chloro-4-cyanomethylaniline as a starting material, the same procedure of Example 252 gave 614 mg of the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.21(2H, brs), 2.61(2H, t, J=6.9 Hz), 2.90(2H, t, J=6.9 Hz), 3.96(2H, brs), 6.69-7.09(3H, m)

Example 495 Synthesis of N-(2-(4-amino-3-chlorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 494 as a starting material, the same procedure of Example 253 gave 912 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 2.66(2H, t, J=6.9 Hz), 3.20-3.40(2H, m), 3.97(2H, brs), 4.54(1H, brs), 6.69-7.07(3H, m)

Example 496 Synthesis of N-(2-(3-chloro-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 495 as a starting material, the same procedure of Example 120 gave 114 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.79(2H, t, J=6.9 Hz), 3.33-3.40(2H, m), 4.68(1H, brs), 6.24(2H, brs), 7.15-7.18(1H, m), 7.34-7.39(2H, m), 7.93(1H, brs)

Example 497 Synthesis of N-(2-(3-chloro-4-(S-ethylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 496 as a starting material, the same procedure of Example 95 gave 118 mg of the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 1.40(3H, t, J=7.3 Hz), 1.44(9H, s), 2.73(2H, t, J=6.9 Hz), 2.96-3.20(2H, m), 3.31-3.35(2H, m), 4.52(1H, brs), 6.92-7.04(2H, m), 7.22(1H, s)

Example 498 Synthesis of N-(2-(3-chloro-4-(S-ethylisothioureido)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 497 as a starting material, the same procedure of Example 5 gave 95 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.44(3H, t, J=7.3 Hz), 3.07(2H, t, J=7.3 Hz), 3.22-3.35(4H, m), 7.40-7.49(2H, m), 7.62(1H, s)

Example 499 Synthesis of N-(2-fluoro-4-methylphenyl)phthalimide

Using 2-fluoro-4-methylaniline as a starting material, the same procedure of Example 248 gave 8.8 g of the titled compound (yield, 22%).

¹H-NMR(CDCl₃) δ: 2.42(3H, s), 7.06-7.26(3H, m), 7.78-7.81(2H, m), 7.94-7.97(2H, m)

Example 500 Synthesis of N-(4-bromomethyl-2-fluorophenyl)phthalimide

Using the compound obtained in Example 499 as a starting material, the same procedure of Example 249 gave 6.0 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 4.49(2H, s), 7.30-7.38(3H, m), 7.80-7.83(2H, m), 7.96-7.99(2H, m)

Example 501 Synthesis of N-(4-cyanomethyl-2-fluorophenyl)phthalimide

Using the compound obtained in Example 500 as a starting material, the same procedure of Example 250 gave 2.0 g of the titled compound (yield, 40%).

¹H-NMR(CDCl₃) δ: 3.84(2H, s), 7.27-7.47(3H, m), 7.79-7.84(2H, m), 7.96-8.00(2H, m)

Example 502 Synthesis of 4-cyanomethyl-2-fluoroaniline

Using the compound obtained in Example 501 as a starting material, the same procedure of Example 251 gave 290 mg of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 3.62(2H, s), 3.78(2H, brs), 6.72-6.97(3H, m)

Example 503 Synthesis of 4-(2-aminoethyl)-2-fluoroaniline

Using the compound obtained in Example 502 as a starting material, the same procedure of Example 252 gave 290 mg of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.21(2H, brs), 2.62(2H, t, J=6.9 Hz), 2.90(2H, t, J=6.9 Hz), 3.64(2H, brs), 6.67-6.85(3H, m)

Example 504 Synthesis of N-(2-(4-amino-3-fluorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 503 as a starting material, the same procedure of Example 253 gave 290 mg of the titled compound (yield, 65%).

¹H-NMR(CDCl₃) δ: 1.44(9H, s), 2.67(2H, t, J=6.9 Hz), 2.65-2.75(2H, m), 3.64(2H, brs), 4.53(1H, brs), 6.68-6.84(3H, m)

Example 505 Synthesis of N-(2-(3-fluoro-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 504 as a starting material, the same procedure of Example 120 gave 88 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 2.80(2H, t, J=6.9 Hz), 3.33-3.40(2H, m), 4.62(1H, brs), 6.15(2H, brs), 7.03-7.06(2H, m), 7.29-7.35(1H, m), 7.74(1H, brs)

Example 506 Synthesis of N-(2-(4-(S-ethylisothioureido)-3-fluorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 505 as a starting material, the same procedure of Example 95 gave 79 mg of the titled compound (yield, 83%).

¹H-NMR(CDCl₃) δ: 1.37(3H, t, J=7.3 Hz), 1.44(9H, s), 2.74(2H, t, J=6.9 Hz), 2.95-3.20(2H, m), 3.28-3.44(2H, m), 4.53(1H, brs), 6.85-7.00(3H, m)

Example 507 Synthesis of N-(2-(4-(S-ethylisothioureido)-3-fluorophenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 506 as a starting material, the same procedure of Example 5 gave 44 mg of the titled compound (yield, 64%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.07(2H, t, J=7.3 Hz), 3.20-3.34(4H, m), 7.25-7.45(3H, m)

Example 508 Synthesis of 2-(5-methoxy-2-nitrophenyl)ethylamine

To a solution of 2-(3-methoxyphenyl)ethylamine (1.51 g) in chloroform (30 ml), fuming nitric acid (specific gravity=1.52; 0.84 ml) and sulfuric acid (1.07 ml) were successively added dropwise under ice cooling and stirred under ice cooling for 3 h. Water and 2 N aqueous sodium hydroxide solution were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 400 mg of the titled compound (yield, 21%)

¹H-NMR(CDCl₃) δ: 1.51(2H, brs), 3.00-3.20(4H, m), 3.89(3H, s), 6.81-6.84(2H, m), 8.04-8.08(1H, m)

Example 509 Synthesis of N-(2-(5-methoxy-2-nitrophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 508 as a starting material, the same procedure of Example 22 gave 448 mg of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.43(9H, s), 3.14(2H, t, J=6.9 Hz), 3.42-3.50(2H, m), 3.88(3H, s), 4.73(1H, brs), 6.82-6.86(2H, m), 8.05-8.08(1H, m)

Example 510 Synthesis of N-(2-(2-amino-5-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 509 as a starting material, the same procedure of Example 2 gave 300 mg of the titled compound (yield, 75%).

¹H-NMR(CDCl₃) δ: 1.45(9H, s), 2.70(2H, t, J=6.9 Hz), 3.27-3.35(2H, m), 3.74(3H, s), 4.82(1H, brs), 6.62-6.64(3H, m)

Example 511 Synthesis of N-(2-(5-methoxy-2-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 510 as a starting material, the same procedure of Example 120 gave 170 mg of the titled compound quantitatively.

1H-NMR(CDCl₃) δ: 1.34(9H, s), 2.76(2H, t, J=6.9 Hz), 3.28-3.40(2H, m), 3.79(3H, s), 4.82(1H, brs), 6.32(2H, brs), 6.78-6.81(2H, m), 7.15-7.27(1H, m), 8.03(1H, brs)

Example 512 Synthesis of N-(2-(2-(S-ethylisothioureido)-5-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 511 as a starting material, the same procedure of Example 95 gave 54 mg of the titled compound (yield, 82%).

¹H-NMR(CDCl₃) δ: 1.37(3H, t, J=7.3 Hz), 1.40(9H, s), 2.67(2H, t, J=6.6 Hz), 3.00-3.20(2H, m), 3.28-3.40(2H, m), 3.77(3H, s), 5.30(1H, brs), 6.70-6.81(3H, m)

Example 513 Synthesis of N-(2-(2-(S-ethylisothioureido)-5-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 512 as a starting material, the same procedure of Example 5 gave 52 mg of the titled compound quantitatively.

¹H -NMR(D₂O) δ: 1.40-1.50(3H, m), 2.94(2H, t, J=7.6 Hz), 3.19-3.25(4H, m), 3.87(3H, s), 7.00-7.10(2H, m), 7.30-7.34(1H, m)

Example 514 Synthesis of N-(2-(5-methoxy-2-(N′-nitroguanidino)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 510 as a starting material, the same procedure of Example 6 gave 59 mg of the titled compound (yield, 57%).

¹H-NMR(CDCl₃) δ: 1.29(9H, s), 2.77(2H, t, J=6.3 Hz), 3.30-3.37(2H, m), 3.81(3H, s), 4.78(1H, brs), 6.79-6.85(2H, m), 7.19-7.22(1H, m)

Example 515 Synthesis of N-(2-(5-methoxy-2-(N′-nitroguanidino)phenyl)ethyl)amine hydrochloride

Using the compound obtained in Example 514 as a starting material, the same procedure of Example 5 gave 45 mg of the titled compound quantitatively.

¹H-NMR(D₂O) δ: 2.97(2H, t, J=7.9 Hz), 3.22(2H, t, J=7.9 Hz), 3.87(3H, s), 7.00-7.06(2H, m), 7.31-7.34(1H, m)

Example 516 Synthesis of N-(2-(2-(N′-t-butoxycarbonyl-N″-ethylguanidino)-5-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 510 as a starting material, the same procedure of Example 233 gave 112 mg of the titled compound (yield, 90%).

¹H-NMR(CDCl₃) δ: 0.96-1.18(3H, m), 1.35(9H, s), 1.54(9H, s), 2.70-2.72(2H, m), 3.28-3.41(4H, m), 3.79(3H, s), 4.67(1H, brs), 6.70-6.82(2H, m), 7.02-7.20(1H, m), 8.02(1H, brs)

Example 517 Synthesis of N-(2-(2-(N′-ethylguanidino)-5-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 516 as a starting material, the same procedure of Example 5 gave 70 mg of the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 2.96(2H, t, J=7.6 Hz), 3.20-3.34(4H, m), 3.87(3H, s), 7.00-7.10(2H, m), 7.28-7.32(1H, m)

Example 518 Synthesis of N-(4-hydroxymethyl-2-methylphenyl)carbamic acid t-butyl ester

Lithium aluminum hydride (5.02 g) was suspended in tetrahydrofuran (300 ml). To the suspension, 4-amino-3-methylbenzoic acid (10.53 g) was added slowly at room temperature and the reaction mixture was heated under reflux for 3 h. After addition of ethyl acetate and water, the reaction mixture was stirred for 30 min and then Celite and anhydrous sodium sulfate were added. The resulting reaction mixture was filtered and the filterate was concentrated under reduced pressure to give a crude procudt. Then, water, sodium hydroxide (3.07 g) and di-t-butyl dicarbonate (15.2 g) were successively added to the crude product, which was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture and, after washing with water once, the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexne:ethyl acetate=5:1) to give 7.658 g of the titled compound (yield, 46%).

¹H-NMR(CDCl₃) δ: 7.77(1H, d, J=9.0 Hz), 7.22-7.13(2H, m), 6.27(1H, brs), 4.59(2H, s), 2.25(3H, s), 1.79(1H, brs), 1.52(9H, s)

Example 519 Synthesis of N-(4-bromomethyl-2-methylphenyl)carbamic acid t-butyl ester

The compound (1.035 g) obtained in Example 518 was dissolved in methylene chloride (20 ml) and to the solution, triphenylphosphine (1.38 g) and carbon tetrabromide (1.74 g) were successively added under ice cooling. The reaction mixture was stirred for 30 min under ice cooling, then stirred at room temperature for 30 min and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:1) to give 476.6 mg of the titled compound (yield, 36%).

¹H-NMR(CDCl₃) δ: 7.84(1H, d, J=8.1 Hz), 7.29-7.15(2H, m), 6.28(1H, brs), 4.46(2H, s), 2.24(3H, s), 1.52(9H, s)

Example 520 Synthesis of N-(4-cyanomethyl-2-methylphenyl)carbamic acid t-butyl ester

The compound (155.1 mg) obtained in Example 519 was dissolved in dimethyl sulfoxide (5 ml). To the solution, sodium cyanide (127 mg) was added and the mixture was heated at 50° C. under stirring for 10 min. To the resulting reaction mixture, ethyl acetate was added and the organic layer was washed with water twice, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 77.7 mg of the titled compound (yield, 61%).

¹H-NMR(CDCl₃) δ: 7.84(1H, d, J=8.8 Hz), 7.17-7.08(2H, m), 6.28(1H, brs), 3.67(2H, s), 2.25(3H, s), 1.52(9H, s)

Example 521 Synthesis of 4-cyanomethyl-2-methylaniline

The compound (1.16 g) obtained in Example 520 was dissolved in methylene chloride (15 ml); to the solution, trifluoroacetic acid (4 ml) was added and the mixture was stirred at room temperature for 1 h. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with methylene chloride. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 480.5 mg of the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 7.06-6.93(2H, m), 6.65(1H, d, J=8.1 Hz), 3.67(2H, brs), 3.61(2H, s), 2.16(3H, s)

Example 522 Synthesis of 4-(2-aminoethyl)-2-methylaniline

Using the compound obtained in Example 521 as a starting material, the same procedure of Example 252 gave 486.5 mg of the titled compound (yield, 100%).

¹H-NMR(CDCl₃) δ: 6.93-6.83(2H, m), 6.62(1H, d, J=8.3 Hz), 3.52(2H, brs), 2.90(2H, t, J=6.8 Hz), 2.62(2H, t, J=6.8 Hz), 2.15(3H, s), 1.69(2H, brs)

Example 523 Synthesis of N-(2-(4-amino-3-methylphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 522 as a starting material, the same procedure of Example 253 gave 477.4 mg of the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 6.91-6.83(2H, m), 6.62(1H, d, J=7.8 Hz), 4.52(1H, brs), 3.53(2H, brs), 3.31(2H, dt, J=5.4, 7.3 Hz), 2.66(2H, t, J=7.3 Hz), 2.15(3H, s), 1.44(9H, s)

Example 524 Synthesis of N-(2-(3-methyl-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 523 as a starting material, the same procedure of Example 120 gave 82.7 mg of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 7.84(1H, brs), 7.20-7.04(3H, m), 6.00(2H, brs), 4.62(1H, brs), 3.36(2H, dt, J=6.3, 6.6 Hz), 2.77(2H, t, J=6.6 Hz), 2.29(3H, s), 1.43(9H, s)

Example 525 Synthesis of N-(2-(4-(S-ethylisothioureido)-3-methylphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 524 as a starting material, the same procedure of Example 27 gave 82.4 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 7.00(1H, s), 6.96(1H, d, J=8.0 Hz), 6.75(1H, d, J=8.0 Hz), 4.52(1H, brs), 4.37(1H, brs), 3.34(2H, dt, J=6.3, 6.6 Hz), 3.20-2.95(2H, m), 2.71(2H, t, J=6.6 Hz), 2.13(3H, s), 1.44(9H, s), 1.38(3H, t, J=7.3 Hz)

Example 526 Synthesis of N-(2-(4-(S-ethylisothioureido)-3-methylphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 525 as a starting material, the same procedure of Example 5 gave 75.5 mg of the titled compound (yield, 100%).

¹H-NMR(DMSO-d₆) δ: 11.55(1H, brs), 9.50(2H, brs), 8,23(3H, brs), 7.28(1H, s), 7.20(2H, s), 3.45-3.23(2H, m), 3.15-2.87(4H, m), 2.19(3H, s), 1.30(3H, t, J=7.1 Hz)

Example 527 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 49 as a starting material, the same procedure of Example 233 gave 74.4 mg of the titled compound (yield, 10%).

¹H-NMR(CDCl₃) δ: 1.03-1.16(3H, m), 1.43(9H, s), 1.51(9H, s), 2.76-2.82(2H, m), 3.27-3.46(4H, m), 4.62(1H, brs), 6.98-7.28(5H, m)

MS(m/z)406(M⁺)

Example 528 Synthesis of N-(2-(4-(N′-ethylguanidino)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 527 as a starting material, the same procedure of Example 5 gave 44.6 mg of the titled compound (yield, 89%).

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 3.03(2H, t, J=7.3 Hz), 3.25-3.35(4H, m), 7.29(2H, d, J=8.6 Hz), 7.40(2H, d, J=8.6 Hz)

MS(m/z)206(M⁺)

Example 529 Synthesis of N-(3-amino-2-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 127 as a starting material, the same procedure of Example 2 gave 4.4 g of the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.43(18H, s), 2.03(3H, s), 3.45(2H, brs), 4.74(2H, s), 6.43-6.98(3H, m)

MS(m/z)336(M⁺)

Example 530 Synthesis of N-(2-methyl-3-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 529 as a starting material, the same procedure of Example 120 gave 1.896 g of the titled compound (yield, 86%).

1H-NMR(CDCl₃) δ: 1.46(18H, s), 2.25(3H, s), 4.80(2H, s), 5.83(2H, brs), 7.15(2H, d, J=7.6 Hz), 7.23-7.29(1H, m), 7.80(1H, s)

Example 531 Synthesis of N-(3-(di-(t-butoxycarbonyl)aminomethyl)-2-methylphenyl)amidinosulfonic acid

Using the compound obtained in Example 530 as a starting material, the same procedure of Example 277 gave 1.96 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.48(18H, s), 2.22(3H, s), 4.80(2H, s), 7.13-7.24(2H, m), 7.28-7.36(1H, m),

Example 532 Synthesis of N-(3-(N′-ethylguanidino)-2-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 531 as a starting material and also using ethylamine hydrochloride as a reagent, the same procedure of Example 278 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.17(3H, t, J=7.2 Hz), 1.43(18H, s), 2.09(3H, s), 3.24(2H, q, J=7.2 Hz), 3.89(2H, brs), 4.76(2H, s), 6.72-6.79(2H, m), 7.02-7.10(1H, m), 7.28(1H, s)

MS(m/z)406(M⁺)

Example 533 Synthesis of N-(3-(N′-ethylguanidino)-2-methylphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 532 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 2.28(3H, s), 3.31(2H, q, J=7.3 Hz), 4.29(2H, s), 7.32-7.46(3H, m)

MS(m/z)206(M⁺)

Example 534 Synthesis of N-(3-(N′-ethyl-N′-methylguanidino)-2-methylphenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 531 as a starting material, the same procedure of Example 304 gave 77.6 mg of the titled compound (yield, 27%).

¹H-NMR(CDCl₃) δ: 1.19(3H, t, J=6.9 Hz), 1.43(18H, s), 2.08(3H, s), 2.96(3H, s), 3.41(2H, q, J=6.9 Hz), 4.77(2H, s), 6.73(2H, t, J=7.6 Hz), 7.05(1H, t, J=7.6 Hz)

MS(m/z)420(M⁺)

Example 535 Synthesis of N-(3-(N′-ethyl-N′-methylguanidino)-2-ethylphenylmethyl)amine dihydrochloide

Using the compound obtained in Example 534 as a starting material, the same procedure of Example 5 gave 42.7 mg of the titled compound (yield, 81%).

¹H-NMR(D₂O) δ: 1.28(3H, t, J=7.3 Hz), 2.27(3H, s), 3.15(3H, s), 3.52(2H, q, J=7.3 Hz), 4.30(2H, s), 7.34(1H, dd, J=7.6, 2.0 Hz), 7.41-7.48(2H, m)

MS(m/z)220(M⁺)

Example 536 Synthesis of N-(2-chloro-3-(di-(t-butoxycarbonyl)aminomethyl)phenyl)amidinosulfonic acid

Using the compound obtained in Example 135 as a starting material, the same procedure of Example 277 gave 0.68 g of the titled compound (yield, 97%).

¹H-NMR(CDCl₃) δ: 1.45(18H, s), 4.90(2H, s), 7.22-7.29(1H, m), 7.38-7.46(2H, m)

Example 537 Synthesis of N-(2-chloro-3-(N′-ethylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 536 as a starting material, the same procedure of Example 442 gave the titled compound quantitatively.

1H-NMR(CDCl₃) δ: 1.20(3H, t, J=7.3 Hz), 1.45(18H, s), 3.28(2H, q, J=7.3 Hz), 4.89(2H, s), 6.77(1H, d, J=7.7 Hz), 6.87(1H, d, J=7.7 Hz), 7.13(1H, t, J=7.7 Hz)

MS(m/z)426(M⁺)

Example 538 Synthesis of N-(2-chloro-3-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 537 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 3.33(2H, q, J=7.3 Hz), 4.39(2H, s), 7.51-7.62(3H, m)

MS(m/z)226(M⁺)

Example 539 Synthesis of N-(2-chloro-3-(N′-ethyl-N′-methylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 536 as a starting material, the same procedure of Example 304 gave 0.12 g of the titled compound (yield, 38%).

¹H-NMR(CDCl₃) δ: 1.21(3H, t, J=6.9 Hz), 1.44(18H, s), 2.98(3H, s), 3.43(2H, q, J=6.9 Hz), 3.85(1H, brs), 4.88(2H, s), 6.75(1H, d, J=7.6 Hz), 6.84(1H, d, J=7.6 Hz), 7.11(1H, t, J=7.6 Hz)

MS(m/z)440(M⁺)

Example 540 Synthesis of N-(2-chloro-3-(N′-ethyl-N′-methylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 539 as a starting material, the same procedure of Example 5 gave 76.2 mg of the titled compound (yield, 90%).

¹H-NMR(D₂O) δ: 1.28(3H, t, J=7.3 Hz), 3.16(3H, s), 3.53(2H, q, J=7.3 Hz), 4.40(2H, s), 7.51-7.60(3H, m)

MS(m/z)240(M⁺)

Example 541 Synthesis of N-(3-(t-butoxycarbonylaminoethyl)phenyl)amidinosulfonic acid

Using the compound obtained in Example 58 as a starting material, the same procedure of Example 277 gave 1.99 g of the titled compound (yield, 80%).

¹H-NMR(DMSO-d₆) δ: 1.35(9H, s), 2.74(2H, t, J=6.9 Hz), 3.12-3.33(2H, m), 6.74(1H, brs), 7.10-7.20(3H, m),7.39(1H, t, J=7.6 Hz), 9.08(1H, brs), 9.63(1H, s), 11.45(1H, s)

Example 542 Synthesis of N-(3-(N′-ethylguanidino)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 541 as a starting material, the same procedure of Example 442 gave 0.415 g of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.16-1.21(3H, m), 1.46(9H, s), 2.68-2.81(2H, m), 3.22-3.47(4H, m), 4.95(2H, brs), 5.35(1H, brs), 6.81-6.85(3H, m), 7.15-7.22(1H, m)

MS(m/z)306(M⁺)

Example 543 Synthesis of N-(3-(N′-ethylguanidino)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 542 as a starting material, the same procedure of Example 5 gave 0.356 g of the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 3.03(2H, t, J=7.3 Hz), 3.26-3.36(4H, m), 7.22-7.25(2H, m), 7.31(1H, d, J=8.3 Hz), 7.47(1H, d, J=8.6 Hz)

MS(m/z)206(M⁺)

Example 544 Synthesis of N-(3-(N′-ethyl-N′-methylguanidino)phenylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 541 as a starting material, the same procedure of Example 304 gave 126.5 mg of the titled compound (yield, 27%).

¹H-NMR(CDCl₃) δ: 1.17(3H, t, J=6.9 Hz), 1.40(9H, s), 2.70(2H, t, J=6.9 Hz), 2.93(3H, s), 3.33-3.41(4H, m), 3.86(2H, br), 4.74(1H, brs), 6.65-6.78(3H, m), 7.16(1H, t, J=7.6 Hz)

FAB-MS(m/z)321(M⁺+1)

Example 545 Synthesis of N-(3-(N′-ethyl-N′-methylguanidino)phenylethyl)amine dihydrochloride

Using the compound obtained in Example 544 as a starting material, the same procedure of Example 5 gave 106 mg of the titled compound (yield, 93%).

¹H-NMR(D₂O) δ: 1.26(3H, t, J=7.3 Hz), 3.03(2H, t, J=7.3 Hz), 3.13(3H, s), 3.30(2H, t, J=7.3 Hz), 3.50(2H, q, J=7.3 Hz), 7.21-7.23(2H, m), 7.31(1H, d, J=7.9 Hz), 7.48(1H, t, J=8.2 Hz)

MS(m/z)220(M⁺)

Example 546 Synthesis of N-(5-nitro-2-piperidinophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using piperidine as a reagent in the absence of a solvent, the same procedure of Example 264 gave 1.524 g of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.45(18H, s), 1.60-1.79(6H, m), 2.91-2.95(4H, m), 4.82(2H, s), 7.04(1H, d, J=8.6 Hz), 8.00(1H, d, J=2.3 Hz), 8.09(1H, dd, J=8.6, 2.3 Hz)

FAB-MS(m/z)436(M⁺+1)

Example 547 Synthesis of N-(5-amino-2-piperidinophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 546 as a starting material, the same procedure of Example 2 gave 1.01 g of the titled compound (yield, 72%).

¹H-NMR(CDCl₃) δ: 1.41(18H, s), 1.43-1.72(6H, m), 2.65-2.73(4H, m), 3.45(2H, br), 4.84(2H, s), 6.44(1H, d, J=2.6 Hz), 6.52(1H, dd, J=8.3, 2.6 Hz), 6.89(1H, d, J=8.3 Hz)

FAB-MS(m/z)406(M⁺+1)

Example 548 Synthesis of N-(2-piperidino-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 547 as a starting material, the same procedure of Example 120 gave 0.59 g of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.44(18H, s), 1.56-1.79(6H, m), 2.78-2.83(4H, m), 4.83(2H, s), 5.99(2H, brs), 6.93-6.94(1H, m), 7.05-7.06(2H, m), 7.72(1H, brs)

MS(m/z)464(M⁺)

Example 549 Synthesis of N-(5-(S-ethylisothioureido)-2-piperidinophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 548 as a starting material, the same procedure of Example 95 gave 0.271 g of the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 1.26(3H, t, J=7.3 Hz), 1.41(18H, s), 1.48-1.73(6H, m), 2.67-2.85(4H, m), 2.92-3.13(2H, m), 4.82(1H, br), 4.86(2H, s), 6.62-6.78(2H, m), 7.00(1H, d, J=8.3 Hz)

MS(m/z)492(M⁺)

Example 550 Synthesis of N-(5-(S-ethylisothioureido)-2-piperidinophenylmethyl)amine trihydrochloride

Using the compound obtained in Example 549 as a starting material, the same procedure of Example 5 gave 128.4 mg of the titled compound (yield, 58%).

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 1.67-1.85(2H, m), 1.94-2.11(4H, m), 3.24(2H, q, J=7.3 Hz), 3.40-3.69(4H, m), 4.42(2H, s), 7.56-7.68(2H, m), 7.78-7.92(1H, m)

MS(m/z)292(M⁺)

Example 551 Synthesis of N-(3-(di-(t-butoxycarbonyl)aminomethyl)-4-piperidinophenyl)amidinosulfonic acid

Using the compound obtained in Example 548 as a starting material, the same procedure of Example 277 gave 152 mg of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.42(18H, s), 1.50-1.73(6H, m), 2.67-2.85(4H, m), 4.83(2H, s), 7.06(1H, s), 7.15(1H, d, J=8.6 Hz), 7.22-7.32(1H, m)

Example 552 Synthesis of N-(5-(N′-ethylguanidino)-2-piperidinophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 551 as a starting material, the same procedure of Example 442 gave 0.11 g of the titled compound (yield, 53%).

¹H-NMR(CDCl₃) δ: 1.17(3H, t, J=7.3 Hz), 1.40(18H, s), 1.47-1.75(6H, m), 2.68-2.83(4H, m), 3.21(2H, q, J=7.3 Hz), 4.84(2H, s), 6.69(1H, s), 6.75(1H, d, J=8.3 Hz), 6.97(1H, d, J=8.3 Hz)

MS(m/z)475(M⁺)

Example 553 Synthesis of N-(5-(N′-ethylguanidino)-2-piperidinophenylmethyl)amine trihydrochloride

Using the compound obtained in Example 552 as a starting material, the same procedure of Example 5 gave 76.7 mg of the titled compound (yield, 87%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 1.69-1.81(2H, m), 1.97-2.09(4H, m), 3.34(2H, q, J=7.3 Hz), 3.51(4H, t, J=5.6 Hz), 4.39(2H, s), 7.48(1H, d, J=2.3 Hz), 7.53(1H, dd, J=8.9, 2.3 Hz), 7.77(1H, d, J=8.9 Hz)

FAB-MS(m/z)276(M⁺+1)

Example 554 Synthesis of N-(2-chloro-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using 2-chloro-5-nitrobenzyl bromide as a starting material, the same procedure of Example 127 gave 3.5 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.49(9H, s), 1.50(9H, s), 4.95(2H, s), 7.53(1H, dd, J=5.6, 3.2 Hz), 8.02-8.13(2H, m)

FAB-MS(m/z)387(M⁺+1)

Example 555 Synthesis of N-(5-amino-2-chlorophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 554 as a starting material and also using Raney nickel as a catalyst, the same procedure of Example 2 gave 3.17 g of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.48(18H, s), 3.69(2H, brs), 4.82(2H, s), 6.47(1H, s), 6.49-6.52(1H, m), 7.08(1H, d, J=7.6 Hz)

MS(m/z)356(M⁺)

Example 556 Synthesis of N-(2-chloro-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 555 as a starting material, the same procedure of Example 120 gave 0.45 g of the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.48(18H, s), 4.87(2H, s), 6.12(2H, brs), 7.04(1H, s), 7.09(1H, d, J=8.6 Hz),7.41(1H, d, J=8.6 Hz), 8.03(1H, brs)

MS(m/z)415(M⁺)

Example 557 Synthesis of N-(2-chloro-5-(S-ethylisothioureido)phenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 556 as a starting material, the same procedure of Example 95 gave 0.37 g of the titled compound (yield, 99%).

¹H-NMR(CDCl₃) δ: 1.26(3H, t, J=7.3 Hz), 1.44(9H, s), 4.12(2H, q, J=7.3 Hz), 4.35(2H. d, J=5.9 Hz), 5.00(1H, brs), 6.68-6.83(1H, m), 6.93(1H, s), 7.21-7.33(1H, m)

FAB-MS(m/z)343(M⁺+1)

Example 558 Synthesis of N-(2-chloro-5-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 557 as a starting material, the same procedure of Example 5 gave 198.3 mg of the titled compound (yield, 59%).

¹H-NMR(D₂O) δ: 1.42(3H, t, J=7.3 Hz), 3.25(2H, q, J=7.3 Hz), 4.38(2H, s), 7.47(1H, dd, J=8.6, 2.6 Hz), 7.55(1H, d, J=2.6 Hz), 7.71(1H, d, J=8.6 Hz)

FBA-MS(m/z)244(M⁺+1)

Example 559 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-chlorophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 555 as a starting material, the same procedure of Example 233 gave 0.159 g of the titled compound (yield, 52%).

¹H-NMR(CDCl₃) δ: 1.07-1.40(3H, m), 1.46(18H, s), 1.48(9H, s), 3.38-3.43(2H, m), 4.87(2H, s), 6.75-6.98(1H, m), 7.28-7.42(2H, m)

FAB-MS(m/z)527(M⁺+1)

Example 560 Synthesis of N-(2-chloro-5-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 559 as a starting material, the same procedure of Example 5 gave 62.2 mg of the titled compound (yield, 69%).

¹H-NMR(D₂O) δ: 1.23(3H, t, J=7.3 Hz), 3.33(2H, q, J=7.3 Hz), 4.35(2H, s), 7.38(1H, dd, J=8.6, 2.6 Hz), 7.45(1H, d, J=2.6 Hz), 7.64(1H, d, J=8.6 Hz)

FAB-MS(m/z)277(M⁺+1)

Example 561 Synthesis of 2-(2-benzyloxyphenyl)-2-methylpropionic acid methyl ester

Using 2-benzyloxyphenylacetic acid methyl ester as a starting material and also using potassium t-butoxide as a base, the same procedure of Example la gave 2-(2-benzyloxyphenyl)propioic acid methyl ester. Using lithium diisopropylamide as a base, the resulting 2-(2-benzyloxyphenyl)propionic acid methyl ester was further treated as in Example la to give 4.72 g of the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.58(6H, s), 3.42(3H, s), 5.07(2H, s), 6.91(1H, dd, J=7.3, 1.2 Hz), 6.99(1H, dd, J=7.3, 1.2 Hz), 7.21(1H, dd, J=7.9, 1.8 Hz), 7.33(1H, dd, J=7.9, 1.8 Hz), 7.35-7.40(5H, m)

Example 562 Synthesis of 2-(2-benzyloxy-5-nitrophenyl)-2-methylpropionic acid methyl ester

To a mixture of sulfuric acid (0.27 ml) and nitric acid (0.34 ml), a solution of the compound (1.0 g) obtained in Example 561 in acetic acid (30 ml) was added dropwise at 5° C. The reaction mixture was stirred at 45° C. for 4 h, poured into ice cold water and ethyl acetate was added to the mixture. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=9:1) to give 530 mg of the titled compound (yield, 46%).

¹H-NMR(CDCl₃) δ: 1.60(6H, s), 3.42(3H, s), 5.29(2H, s), 6.99(1H, d, J=9.2 Hz), 7.33-7.45(5H, m), 8.16(1H, dd, J=9.2, 3.1 Hz), 8.25(1H, d, J=3.1 Hz)

Example 563 Synthesis of 2-(2-benzyloxy-5-nitrophenyl)-2-methylpropionic acid

To the compound (1.54 g) obtained in Example 562 in 1, 4-dioxane (20 ml) was added an aqueous lithium hydroxide solution (1.0M, 47 ml). The reaction mixture was heated under reflux at 100° C. for 12 h and then 2 N HCl and ethyl acetate were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 1.355 g of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.60(6H, s), 5.02(2H, s), 6.91(1H, d, J=9.2 Hz), 7.30-7.37(5H, m), 8.16(1H, dd, J=9.2, 3.1 Hz), 8.25(1H, d, J=3.1 Hz)

Example 564 Synthesis of N-(1-(2-benzyloxy-5-nitrophenyl)-1-methylethyl)amine

To a mixture of the compound (1.6 g) obtained in Example 563, methylene chloride (20 ml) and triethylamine (0.92 ml), diphenylphosphorylazide (1.37 ml) was added. The reaction mixture was stirred at room temperature for 10 h and 2 N HCl and chloroform were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the resulting residue, water (16 ml) and 1,4-dioxane (32 ml) were added. The reaction mixture was heated under reflux for 2 h and 2 N HCl and chloroform were added. After adding 2 N aqueous sodium hydroxide solution and chloroform to the aqueous layer, the organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 1.09 g of the titled compound (yield, 75%).

¹H-NMR(CDCl₃) δ: 1.58(6H, s), 2.01(2H, brs), 5.25(2H, s), 7.03(1H, d, J=9.2 Hz), 7.37-7.45(5H, m), 8.13(1H, dd, J=9.2, 3.1 Hz), 8.35(1H, d, J=3.1 Hz)

Example 565 Synthesis of N-(1-(2-benzyloxy-5-nitrophenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 564 as a starting material and also using potassium carbonate as a base, the same procedure of Example 63 gave 828 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.34(9H, s), 1.71(6H, s), 5.07(1H, brs), 5.18(2H, s), 7.00(1H, d, J=9.2 Hz), 7.35-7.48(5H, m), 8.13(1H, dd, J=9.2, 3.1 Hz), 8.29(1H, d, J=3.1 Hz)

Example 566 Synthesis of N-(1-(5-amino-2-benzyloxyphenyl)-1-methylethyl)carbamic acid t-butyl ester

To a mixture of the compound (100 mg) obtained in Example 565, nickel (II) chloride hexahydrate (123 mg) and methanol (6 ml), sodium borohydride (39 mg) was added. The reaction mixture was stirred at room temperature for 10 min; then, 2 N HCl was added and a saturated aqueous sodium bicarbonate solution and chloroform were also added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:2) to give 87 mg of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.34(9H, s), 1.66(6H, s), 2.80(2H, br), 4.99(2H, s), 5.27(1H, brs), 6.54(1H, dd, J=8.6, 2.4 Hz), 6.74(1H, d, J=2.4 Hz), 6.78(1H, d, J=8.6 Hz), 7.29-7.49(5H, m)

Example 567 Synthesis of N-(1-(2-benzyloxy-5-(N′-nitroguanidino)phenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 566 as a starting material, the same procedure of Example 6 gave 110 mg of the titled compound (yield, 89%).

¹H-NMR(CDCl₃) δ: 1.36(9H, s), 1.69(6H, s), 5.11(2H, s), 7.01(1H, d, J=8.5 Hz), 7.18(1H, dd, J=8.5, 2.4 Hz), 7.31(1H, d, J=2.4 Hz), 7.34-7.46(5H, m), 9.35(1H, brs)

Example 568 Synthesis of N-(1-(2-benzyloxy-5-(N′-nitroguanidino)phenyl)-1-methylmethyl)amine

Using the compound obtained in Example 567 as a starting material, the same procedure of Example 34 gave 47.4 mg of the titled compound (yield, 58%).

¹H-NMR(CDCl₃) δ: 1.58(6H, s), 5.16(2H, s), 7.01(1H, d, J=8.5 Hz), 7.16(1H, dd, J=8.5 Hz, 2.4 Hz), 7.34(1H, d, J=2.4 Hz), 7.35-7.46(5H, m)

Example 569 Synthesis of N-(1-(2-benzyloxy-5-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 566 as a starting material, the same procedure of Example 233 gave 106 mg of the titled compound (yield, 72%).

¹H-NMR(CDCl₃) δ: 1.09(3H, t, J=7.3 Hz), 1.34(9H, s), 1.53(9H, s), 1.67(6H, s), 3.34-3.46(2H, m), 4.80(1H, brs), 5.07(2H, s), 5.14(1H, brs), 6.94(1H, d, J=8.6 Hz), 7.02-7.07(1H, m), 7.22(1H,s), 7.32-7.50(5H, m), 10.53(1H, br)

Example 570 Synthesis of N-(1-(2-benzyloxy-5-(N′-ethylguanidino)phenyl)-1-methylethyl)amine

Using the compound obtained in Example 569 as a starting material, the same procedure of Example 34 gave 58 mg of the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 1.16(3H, t, J=7.3 Hz), 1.51(6H, s), 3.23(2H, q, J=7.3 Hz), 3.69(2H, br), 5.09(2H, s), 6.75(1H, dd, J=8.5, 2.4 Hz), 6.89(1H, d, J=8.5 Hz), 6.95(1H, d, J=2.4 Hz), 7.29-7.47(5H, m)

Example 571 Synthesis of N-(1-(2-benzyloxy-5-thioureidophenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 566 as a starting material, the same procedure of Example 120 gave 114 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.35(9H, s), 1.67(6H, s), 5.09(2H, s), 6.16(2H, brs), 6.95(1H, d, J=8.6 Hz), 7.05(1H, dd, J=8.6, 2.4 Hz), 7.27(1H, d, J=2.4 Hz), 7.36-7.46(5H, m), 7.80(1H, brs)

Example 572 Synthesis of N-(1-(2-benzyloxy-5-(S-ethylisothioureido)phenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 571 as a starting material, the same procedure of Example 95 gave 105.5 mg of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.32-1.37(3H, m), 1.34(9H, s), 1.67(6H, s), 3.03(2H, q, J=7.3 Hz), 5.04(2H, s), 5.22(1H, brs), 6.78(1H, dd, J=8.6, 2.4 Hz), 6.90(1H, d, J=8.6 Hz), 6.95(1H, d, J=2.4 Hz), 7.31-7.50(5H, m)

Example 573 Synthesis of N-(1-(2-benzyloxy-5-(S-ethylisothioureido)phenyl)-1-methylethyl)amine

Using the compound obtained in Example 572 as a starting material, the same procedure of Example 34 gave 51 mg of the titled compound (yield, 63%).

¹H-NMR(CDCl₃) δ: 1.32(3H, t, J=7.3 Hz), 1.68(6H, s), 2.97(2H, q, J=7.3 Hz), 5.15(2H, s), 5.63(4H, br), 6.67(1H, d, J=8.5 Hz), 6.77-6.82(2H, m), 7.32-7.42(5H, m)

Example 574 Synthesis of 2-(2-benzyloxy-3-nitrophenyl)-2-methylpropionic acid methyl ester

The same procedure of

Example 562 gave 140 mg of the titled compound (yield, 12%).

¹H-NMR(CDCl₃) δ: 1.57(6H, s), 3.38(3H, s), 4.84(2H, s), 7.20(1H, t, J=7.9 Hz), 7.31-7.45(5H, m), 7.58(1H, dd, J=7.9, 1.8 Hz), 7.75(1H, dd, J=7.9, 1.8 Hz)

Example 575 Synthesis of 2-(2-benzyloxy-3-nitrophenyl)-2-methylpropionic acid

Using the compound obtained in Example 574 as a starting material, the same procedure of Example 563 gave 370 mg of the titled compound (yield, 86%).

¹H-NMR(CDCl₃) δ: 1.54(6H, s), 4.83(2H, s), 7.19(1H, t, J=7.9 Hz), 7.29-7.41(5H, m), 7.57(1H, dd, J=7.9, 1.2 Hz), 7.76(1H, dd, J=7.9, 1.2 Hz)

Example 576 Synthesis of N-(1-(2-benzyloxy-3-nitrophenyl)-1-methylethyl)amine

Using the compound obtained in Example 575 as a starting material, the same procedure of Example 564 gave 268 mg of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.52(6H, s), 2.03(2H, s), 5.24(2H, s), 7.14(1H, t, J=7.9 Hz), 7.34-7.49(5H, m), 7.68(1H, dd, J=3.7, 1.8 Hz), 7.71(1H, dd, J=3.7, 1.8 Hz)

Example 577 Synthesis of N-(1-(2-benzyloxy-3-nitrophenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 576 as a starting material, the same procedure of Example 565 gave 329 mg of the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.37(9H, s), 1.69(6H, s), 4.86(2H, s), 5.03(1H, brs), 7.18(1H, t, J=7.9 Hz), 7.33-7.46(3H, m), 7.50-7.66(2H, m), 7.67(1H, dd, J=7.9, 1.8 Hz), 7.73(1H, dd, J=7.9, 1.8 Hz)

Example 578 Synthesis of N-(1-(3-amino-2-benzyloxyphenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 577 as a starting material, the same procedure of Example 566 gave 244 mg of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.35(9H, s), 1.72(6H, s), 3.67(2H, s), 4.96(2H, s), 5.34(1H, br), 6.69(1H, dd, J=7.9, 1.8 Hz), 6.82(1H, dd, J=7.9, 1.8 Hz), 6.90(1H, t, J=7.9 Hz), 7.30-7.46(3H, m), 7.51-7.55(2H, m)

Example 579 Synthesis of N-(1-(2-benzyloxy-3-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 578 as a starting material, the same procedure of Example 233 gave 82.4 mg of the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.03-1.14(3H, m), 1.37(9H, s), 1.20-1.60(9H, m), 1.69(6H, s), 3.15-3.43(2H, m), 4.81-5.16(3H, m), 6.97-7.23(3H, m), 7.30-7.42(3H, m), 7.45-7.53(2H, m)

Example 580 Synthesis of N-(1-(2-benzyloxy-3-(N′-ethylguanidino)phenyl)-1-methylethyl)amine

Using the compound obtained in Example 579 as a starting material, the same procedure of Example 34 gave 46.5 mg of the titled compound (yield, 92%).

¹H-NMR(CDCl₃) δ: 1.12(3H, t, J=7.3 Hz), 1.53(6H, s), 3.19(2H, q, J=7.3 Hz), 5.17(2H, s), 6.86(1H, dd, J=7.9, 1.8 Hz), 6.97(1H, t, J=7.9 Hz), 7.04(1H, dd, J=7.9, 1.8 Hz), 7.25-7.46(3H, m), 7.47-7.49(2H, m)

Example 581 Synthesis of N-(1-(2-benzyloxy-3-thioureidophenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 578 as a starting material, the same procedure of Example 120 gave 94 mg of the titled compound (yield, 99.6%).

¹H-NMR(CDCl₃) δ: 1.34(9H, s), 1.65(6H, s), 4.92(2H, s), 5.13(1H, s), 6.38(2H, brs), 7.11(1H, t, J=7.9 Hz), 7.17-7.21(1H, m), 7.30-7.44(4H, m), 7.56-7.61(2H, m), 8.37(1H, s)

Example 582 Synthesis of N-(1-(2-benzyloxy-3-(S-ethylisothioureido)phenyl)-1-methylethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 581 as a starting material, the same procedure of Example 95 gave 98 mg of the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.28(3H, t, J=7.3 Hz), 1.35(9H, s), 1.68(6H, s), 3.00-3.07(2H, m), 4.52(2H, brs), 4.99(2H, s), 5.17(1H, brs), 6.80-6.85(1H, m), 7.01(1H, t, J=7.9 Hz), 7.11(1H, dd, J=7.9, 1.8 Hz), 7.27-7.42(3H, m), 7.49-7.54(2H, m)

Example 583 Synthesis of N-(1-(2-benzyloxy-3-(S-ethylisothioureido)phenyl)-1-methylethyl)amine

Using the compound obtained in Example 582 as a starting material, the same procedure of Example 34 gave 72 mg of the titled compound (yield, 95%).

¹H-NMR(CDCl₃) δ: 1.30(3H, t, J=7.3 Hz), 1.53(6H, s), 2.12(2H, brs), 2.96-3.08(2H, m), 4.60(1H, brs), 5.10(2H, s), 6.79-6.87(1H, m), 7.00(1H, t, J=7.9 Hz), 7.10(1H, dd, J=7.9, 1.8 Hz), 7.28-7.41(5H, m), 7.47(1H, dd, J=7.9, 1.8 Hz)

Example 584 Synthesis of N-(5-nitro-2-(pyrrolidin-1-yl)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using pyrrolidine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.47(18H, s), 1.95-2.05(4H, m), 3.38-3.42(4H, m), 4.87(2H, s), 6.70-6.80(1H, m), 7.95-8.03(2H, m)

Example 585 Synthesis of N-(5-amino-2-(pyrrolidin-1-yl)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 584 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 98%).

¹H-NMR(CDCl₃) δ: 1.40(18H, s), 1.84-1.88(4H, m), 2.89-2.93(4H, m), 4.50(2H, brs), 4.81(2H, s), 6.45-6.53(2H, m), 6.88(1H, d, J=8.3 Hz)

MS(m/z) 392 (M⁺+1)

Example 586 Synthesis of N-(2-(pyrrolidin-1-yl)-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 585 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.44(18H, s), 1.94-1.97(4H, m), 3.12-3.16(4H, m), 4.78(2H, s), 5.94(2H, brs), 6.91-7.00(3H, m), 7.66(1H, brs)

MS(m/z)450(M⁺)

Example 587 Synthesis of N-(5-(S-ethylisothioureido)-2-(pyrrolidin-1-yl)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 586 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 1.33(3H, t, J=7.3 Hz), 1.41(18H, s), 1.87-1.90(4H, m), 2.90-3.10(4H, m), 4.39-4.69(2H, m), 4.81(2H, s), 6.62-6.82(2H, m), 6.95(1H, d, J=8.1 Hz)

Example 588 Synthesis of N-(5-(S-ethylisothioureido)-2-(pyrrolidin-1-yl)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 587 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 63%).

¹H-NMR(D₂O) δ: 6 1.41(3H, t, J=7.5 Hz), 2.07-2.29(4H, m), 3.25(2H, q, J=7.5 Hz), 3.60-3.83(4H, m), 4.46(2H, s), 7.60-7.82(3H, m)

MS(m/z)278(M⁺)

Example 589 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-(pyrrolidin-1-yl)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 585 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=7.3 Hz), 1.48(18H, s), 1.59(9H, s), 1.93-2.03(4H, m), 3.00-3.10(4H, m), 3.33-3.43(2H, m), 4.58(1H, brs), 4.79(2H, s), 6.90-6.95(3H, m), 10.49(1H, brs)

Example 590 Synthesis of N-(5-(N′-ethylguanidino)-2-(pyrrolidin-1-yl)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 589 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 91%).

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.3 Hz), 2.29-2.31(4H, m), 3.35(2H, q, J=7.3 Hz), 3.84-4.00(4H, m), 4.45(2H, s), 7.51-7.78(3H, m)

Example 591 Synthesis of N-(2-(4-(N′-t-butoxcyarbonyl-N″-ethylguanidino)-3-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 490 as a starting material, the same procedure of Example 233 gave 12 mg of the titled compound (yield, 16%).

¹H-NMR(CDCl₃) δ: 1.05-1.20(3H, m), 1.44(9H, s), 1.52(9H, s), 2.78(2H, t, J=6.9 Hz), 3.32-3.47(4H, m), 3.84(3H, s), 4.57(1H, brs), 6.74-6.92(3H, m)

Example 592 Synthesis of N-(2-(4-(N′-ethylguanidino)-3-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 591 as a starting material, the same procedure of Example 5 gave 8 mg of the titled compound (yield, 94%).

¹H-NMR(D₂O) δ: 1.20(3H, t, J=7.3 Hz), 3.03(2H, t, J=7.3 Hz), 3.24-3.33(4H, m), 3.89(3H, s), 6.99(1H, d, J=7.9 Hz), 7.10(1H, s), 7.27(1H, d, J=7.9 Hz)

Example 593 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-3-chlorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 495 as a starting material, the same procedure of Example 233 gave 27 mg of the titled compound (yield, 17%).

¹H-NMR(CDCl₃) δ: 1.27(3H, t, J=7.3 Hz), 1.44(9H, s), 1.47(9H, s), 2.75(2H, t, J=6.9 Hz), 3.30-3.50(4H, m), 4.53(1H, brs), 7.00-7.30(3H, m)

Example 594 Synthesis of N-(2-(3-chloro-4-(N′-ethylguanidino)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 593 as a starting material, the same procedure of Example 5 gave 17 mg of the titled compound (yield, 88%).

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 3.04(2H, t, J=7.3 Hz), 3.27-3.36(4H, m), 7.33-7.44(2H, m), 7.56(1H, s)

Example 595 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-3-fluorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 504 as a starting material, the same procedure of Example 233 gave 90 mg of the titled compound (yield, 54%)

¹H-NMR(CDCl₃) δ: 1.10-1.32(3H,m), 1.44(9H,s), 1.48(9H,s), 2.77(2H, t, J=6.9 Hz), 3.35-3.46(4H,m), 4.55(1H,brs), 6.90-7.00(3H,m)

Example 596 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-3-fluorophenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 595 as a starting material, the same procedure of Example 5 gave 53 mg of the titled compound (yield, 93%)

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 3.04(2H, t, J=7.3 Hz), 3.27-3.36(4H,m), 7.19-7.41(3H,m)

Example 597 Synthesis of N-(1-(3-(N′-t-butoxycarbonyl)-N″-ethylguanidino)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 9 as a starting material, the same procedure of Example 233 gave 280 mg of the titled compound (yield, 81%)

¹H-NMR(CDCl₃) δ: 1.02-1.20(3H,m), 1.42(12H,brs), 1.51(9H,s), 3.38-3.43(2H,m), 4.64-4.90(2H,m), 6.90-7.20(4H,m)

Example 598 Synthesis of N-(1-(3-(N′-ethylguanidino)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 597 as a starting material, the same procedure of Example 5 gave 54 mg of the titled compound (yield, 88%)

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 1.65(3H, d, J=6.9 Hz), 3.32(2H, q, J=7.3 Hz), 4.57(1H, q, J=6.9 Hz), 7.34-7.60(4H,m)

Example 599 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-3-methylphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 523 as a starting material, the same procedure of Example 233 gave 43.5 mg of the titled compound (yield, 39%)

¹H-NMR(CDCl₃) δ: 10.5(1H,brs), 7.18-7.00(3H,m), 4.57(1H,brs), 4.40(1H,brs), 3.36(2H, dt, J=5.4, 6.4 Hz), 2.76(2H, t, J=6.4 Hz), 2.23(3H,s), 1.52(9H,s), 1.44(9H,s), 1.03-1.19(3H,m)

Example 600 Synthesis of N-(2-(4-(N′-ethylguanidino)-3-methylphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 599 as a starting material, the same procedure of Example 5 gave 28.3 mg of the titled compound (yield, 93%)

¹H-NMR(DMSO-d₆) δ: 9.54(1H,s), 8.00-8.25(4H,m), 7.80(1H,brs), 7.50(2H,brs), 7.23(1H,s), 7.20-7.12(2H,m), 3.34-3.17(2H,m), 3.18-2.82(4H,m), 2.19(3H,s), 1.11(3H, t, J=7.1 Hz)

Example 601 Synthesis of N-(3-chloro-4-hydroxymethylphenyl)carbamic acid t-butyl ester

Water was added to 4-amino-2-chlorobenzyl alcohol (1.0125 g) and, after addition of sodium hydroxide (283 mg) and di-t-butyl dicarbonate (1.543 g) at room temperature, the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture and the organic layer was washed with water once, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 1.0576 g of the titled compound (yield, 64%).

¹H-NMR(CDCl₃) δ: 7.56(1H, d, J=2.1 Hz), 7.35(1H, d, J=8.3 Hz), 7.15(1H, dd, J=2.1, 8.3 Hz), 6.55(1H,s), 4.71(2H,s), 2.01(1H,brs), 1.52(9H,s)

Example 602 Synthesis of N-(3-chloro-4-cyanomethylphenyl)carbamic acid t-butyl ester

The compound (555.3 mg) obtained in Example 601 was dissolved in methylene chloride (10 ml); to the solution, triphenylphosphine (735 mg) and carbon tetrabromide (930 mg) were successively added under ice cooling and the mixture was stirred for 30 minutes, then stirred at room temperature for 30 minutes. Subsequently, the solvent was distilled off under reduced pressure and the resulting residue was dissolved in dimethyl sulfoxide (5 ml); to the solution, potassium cyanide (117.8 mg) was added, heated at 50° C. and stirred for 10 minutes. To the resulting reaction mixture, ethyl acetate was added and the organic layer was washed with water twice, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1) to give 89.6 mg of the titled compound (yield, 16%).

¹H-NMR(CDCl₃) δ: 7.66(1H, d, J=2.2 Hz), 7.39(1H, d, J=8.6 Hz), 7.18(1H, dd, J=2.2, 8.6 Hz), 6.53(1H,brs), 3.78(2H,s), 1.52(9H,s)

Example 603 Synthesis of 3-chloro-4-cyanomethylaniline

Using the compound obtained in Example 602 as a starting material, the same procedure of Example 521 gave 184.7 mg of the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 7.21(1H, d, J=8.1 Hz), 6.73(1H, d, J=2.5 Hz), 6.57(1H, dd, J=2.5, 8.3 Hz), 3.80(2H,brs), 3.71(2H,s)

Example 604 Synthesis of 4-(2-aminoethyl)-3-chloroaniline

Using the compound obtained in Example 603 as a starting material, the same procedure of Example 252 gave 189 mg of the titled compound (yield, 100%).

¹H-NMR(CDCl₃) δ: 7.00(1H, d, J=8.3 Hz), 6.71(1H, d, J=2.4 Hz), 6.52(1H, dd, J=2.4, 8.3 Hz), 3.64(2H,brs), 2.98-2.87(2H,m), 2.83-2.71(2H,m), 1.24(2H,brs)

Example 605 Synthesis of N-(2-(4-amino-2-chlorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 604 as a starting material, the same procedure of Example 253 gave 208.3 mg of the titled compound (yield, 64%).

¹H-NMR(CDCl₃) δ: 6.98(1H, d, J=8.1 Hz), 6.70(1H, d, J=2.4 Hz), 6.52(1H, dd, J=2.4, 8.1 Hz), 4.55(1H,brs), 3.64(2H,brs), 3.32(2H, dt, J=6.6, 6.6 Hz), 2.81(2H, t, J=6.6 Hz), 1.43(9H,s)

Example 606 Synthesis of N-(2-(2-chloro-4-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 605 as a starting material, the same procedure of Example 120 gave 78.9 mg of the titled compound (yield, 100%).

¹H-NMR(CDCl₃) δ: 8.42(1H,brs), 7.38-7.20(2H,m), 7.17-7.04(1H,m), 6.30(2H,brs), 4.69(1H,brs), 3.38(2H, dt, J=6.6, 6.6 Hz), 2.94(2H, t, J=6.6 Hz), 1.42(9H,s)

Example 607 Synthesis of N-(2-(2-chloro-4-(S-ethylisothioureido)phenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 606 as a starting material, the same procedure of Example 27 gave 66.7 mg of the titled compound (yield, 78%).

¹H-NMR(CDCl₃) δ: 7.15(1H, d, J=8.3 Hz), 6.96(1H, d, J=2.2 Hz), 6.77(1H, dd, J=2.2, 8.3 Hz), 4.58(1H,brs), 4.28(2H,brs), 3.36(2H, dt, J=6.6, 6.6 Hz), 3.01(2H, q, J=7.3 Hz), 2.88(2H, t, J=6.6 Hz), 1.44(9H,s), 1.36(3H, t, J=7.3 Hz)

Example 608 Synthesis of N-(2-(2-chloro-4-(S-ethylisothioureido)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 607 as a starting material, the same procedure of Example 5 gave 65.3 mg of the titled compound (yield, 100%).

¹H-NMR(DMSO-d₆) δ: 11.88(1H,brs), 9.58(2H,brs), 8.32(3H,brs), 7.53(1H, d, J=8.1 Hz), 7.52(1H, d, J=2.2 Hz), 4.10-3.60(2H,m), 3.35(2H, q, J=7.3 Hz), 3.14-2.93(2H,m), 1.30(3H, t, J=7.3 Hz)

Example 609 Synthesis of N-(2-(4-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-chlorophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 605 as a starting material, the same procedure of Example 233 gave 71.5 mg of the titled compound (yield, 52%).

¹H-NMR(CDCl₃) δ: 10.70(1H,brs), 7.25-6.72(4H,m), 4.58(1H,brs), 3.47-3.27(4H,m), 2.91(2H, t, J=6.4 Hz), 1.49(9H,s), 1.44(9H,s), 1.19(3H, t, J=7.3 Hz)

Example 610 Synthesis of N-(2-(2-chloro-4-(N′-ethylguanidino)phenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 609 as a starting material, the same procedure of Example 5 gave 51.7 mg of the titled compound (yield, 100%).

¹H-NMR(DMSO-d₆) δ: 9.98(1H,s), 8.35(3H,brs), 8.11(1H,brs), 7.83(2H,brs), 7.44(1H, d, J=8.3 Hz), 7.35(1H, d, J=2.2 Hz), 7.18(1H, dd, J=2.2, 8.3 Hz), 5.00-3.50(2H,m), 3.36-3.15(2H,m), 3.10-2.90(2H,m), 1.13(3H, t, J=7.1 Hz)

Example 611 Synthesis of N-(2-(N-benzyl-N-methylamino)-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 263 as a starting material and also using N-methylbenzylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 56%).

¹H-NMR(CDCl₃) δ: 1.47(18H,s), 2.73(3H,s), 4.19(2H,s), 4.93(2H,s), 7.07(1H, d, J=8.9 Hz), 7.26-7.33(5H,m), 8.03-8.09(2H,m)

Example 612 Synthesis of N-(5-amino-2-(N-benzyl-N-methylamino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 611 as a starting material, the same procedure of Example 566 gave the titled compound (yield, 91%).

¹H-NMR(CDCl₃) δ: 1.43(18H,s), 2.48(3H,s), 3.50(2H,s), 3.91(2H,s), 4.98(2H,s), 6.45-6.47(1H,m), 6.52-6.56(1H,m), 6.98(1H, d, J=8.3 Hz), 7.25-7.40(5H,m)

Example 613 Synthesis of N-(2-(N-benzyl-N-methylamino)-5-thioureidophenylmethyl)iminodicarboxylic acid t-butyl ester

Using the compound obtained in Example 612 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.46(18H,s), 2.59(3H,s), 4.02(2H,s), 4.96(2H,s), 6.03(2H,brs), 6.98-7.00(1H,m), 7.03-7.08(1H,m), 7.16(1H, d, J=8.3 Hz), 7.26-7.37(5H,m), 7.80(1H,brs)

Example 614 Synthesis of N-(2-(N-benzyl-N-methylamino)-5-(S-ethylisothioureido)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 613 as a starting material, treatment was performed as in Example 95 and the resulting compound was processed as in Example 5 to give the titled compound (yield, 95%)

¹H-NMR(D₂O) δ: 1.41(3H, t, J=7.3 Hz), 3.12(3H,s), 3.23(2H, q, J=7.3 Hz), 3.94(2H,s), 4.46(2H,s), 7.20-7.23(2H,m), 7.34-7.46(4H,m), 7.58(1H, dd, J=8.9, 2.6 Hz), 7.76(1H, d, J=8.9 Hz)

Example 615 Synthesis of N-(2-(N-benzyl-N-methylamino)-5-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 612 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 58%).

¹H-NMR(CDCl₃) δ: 1.05-1.11(3H,m), 1.45(18H,s), 1.53(9H,s), 2.58(3H,s), 3.32-3.45(2H,m), 4.01(2H,s), 4.97(2H,s), 6.92-7.17(3H,m), 7.26-7.39(5H,m)

Example 616 Synthesis of N-(2-(N-benzyl-N-methylamino)-5-(N′-ethylguanidino)phenylmethyl)amine trihydrochloride

Using the compound obtained in Example 615 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 89%).

¹H NMR(D₂O) δ: 1.23(3H, t, J=7.6 Hz), 3.23(3H,s), 3.33(2H, q, J=7.6 Hz), 3.82(2H,s), 4.54(2H,s), 7.18-7.25(3H,m), 7.34-7.48(3H,m), 7.53(1H, dd, J=8.9, 2.3 Hz), 7.77(1H, d, J=8.9 Hz)

Example 617 Synthesis of N-(1-(2-methyl-3-nitrophenyl)ethyl)phthalimide

Using 1-(2-methyl-3-nitrophenyl)ethanol as a starting material, the same procedure of Example 179 gave the titled compound (yield, 52%).

¹H-NMR(DMSO-d₆) δ: 1.81(3H, d, J=7.3 Hz), 2.31(3H,s), 5.69(1H, q, J=7.3 Hz), 7.48(1H, dd, J=7.9, 7.9 Hz), 7.75(1H, d, J=7.9 Hz), 7.84(4H,s), 7.97(1H, d, J=7.9 Hz)

Example 618 Synthesis of N-(1-(2-methyl-3-nitrophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 617 as a starting material, the same procedure of Example 309 gave the titled compound (yield, 85%).

¹H-NMR(CDCl₃) δ: 1.40(9H,s), 1.41(3H, d, J=6.3 Hz), 2.46(3H,s), 4.83(1H,brs), 4.98-5.14(1H,m), 7.31(1H, dd, J=7.9, 7.9 Hz), 7.53(1H, d, J=7.9 Hz), 7.61(1H, d, J=7.9 Hz)

Example 619 Synthesis of N-(1-(3-amino-2-methylphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 618 as a starting material, the same procedure of Example 566 gave the titled compound (yield, 70%).

¹H-NMR(CDCl₃) δ: 1.41(3H, d, J=6.3 Hz), 1.42(9H,s), 2.14(3H,s), 3.61(2H,brs), 4.74(1H,brs), 4.98-5.15(1H,m), 6.62(1H, d, J=7.9 Hz), 6.74(1H, d, J=7.9 Hz), 7.02(1H, dd, J=7.9, 7.9 Hz)

Example 620 Synthesis of N-(1-(2-methyl-3-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 619 as a starting material, the same procedure of Example 120 gave the titled compound quantitatively.

¹H-NMR(CDCl₃) δ: 1.39(3H, d, J=6.3 Hz), 1.41(9H,s), 2.33(3H,s), 4.89(1H,brs), 4.90-5.03(1H,m), 7.15(1H, d, J=7.6 Hz), 7.24-7.34(2H,m), 7.71(1H,brs)

Example 621 Synthesis of N-(1-(3-(S-ethylisothioureido)-2-methylphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 620 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.36-1.45(3H,m), 1.40(3H, d, J=7.3 Hz), 1.42(9H,s), 2.16(3H,s), 3.02-3.18(2H,m), 4.36(1H,brs), 4.75(1H,brs), 4.93-5.08(1H,m), 6.73(1H, d, J=7.6 Hz), 6.98(1H, d, J=7.6 Hz), 7.13(1H, dd, J=7.6, 7.6 Hz)

Example 622 Synthesis of N-(1-(3-(S-ethylisothioureido)-2-methylphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 621 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 92%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.3 Hz), 1.62(3H, d, J=6.9 Hz), 2.29(3H,s), 3.24-3.28(2H,m), 4.88(1H, q, J=6.9 Hz), 7.37(1H, dd, J=7.9, 1.3 Hz), 7.50(1H, dd, J=7.9, 7.9 Hz), 7.60(1H, dd, J=7.9, 1.3 Hz)

Example 623 Synthesis of N-(1-(3-(N′-t-butoxycarbonyl)-N″-ethylguanidino)-2-methylphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 619 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 38%).

¹H-NMR(CDCl₃) δ: 1.00-1.20(3H,m), 1.40(3H, d, J=7.3 Hz), 1.41(9H,s), 1.54(9H,s), 2.29(3H,s), 3.36-3.45(2H,m), 4.80(1H,brs), 4.90-5.10(1H,m), 7.10-7.30(2H,m)

Example 624 Synthesis of N-(1-(3-(N′-ethylguanidino)-2-methylphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 623 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 92%).

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 1.62(3H, d, J=6.6 Hz), 2.28(3H,s), 3.31(2H, q, J=7.3 Hz), 4.87(1H, q, J=6.6 Hz), 7.34(1H, dd, J=7.6, 1.3 Hz), 7.45(1H, dd, J=7.6, 7.6 Hz), 7.53(1H, dd, J=7.6, 1.3 Hz)

Example 625 Synthesis of N-benzoyl-4-thioureidobenzylamine

Using 4-amino-N-benzoylbenzylamine as a starting material, the same procedure of Example 120 gave 143.5 mg of the titled compound (yield, 76%).

¹H-NMR(DMSO-d₆) δ: 4.44(2H, d, J=5.9 Hz), 7.20-7.38(5H,m), 7.40-7.58(4H,m), 7.89(1H, d, J=6.6 Hz), 9.03(1H, t, J=5.9 Hz), 9.64(1H,s)

Example 626 Synthesis of N-benzoyl-4-(S-ethylisothioureido)benzylamine

To a mixture of N-benzoyl-4-thioureidobenzylamine (139.1 mg) and acetonitrile (10 ml), ethyl iodide (0.5 ml) was added and heated under reflux for 3 h. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1) to give 134.8 mg of the titled compound (yield, 88%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=6.9 Hz), 2.67(1H,brs), 2.90-3.11(2H,m), 4.46(1H,brs), 4.60(2H, d, J=5.6 Hz), 6.25-6.41(1H,m), 6.91(2H, brd, J=8.3 Hz), 7.29(2H, d, J=8.3 Hz), 7.38-7.53(3H,m), 7.75-7.83(3H,m), 7.79(2H, d, J=6.6 Hz)

Example 627 Synthesis of N-benzoyl-4-(N′-t-butoxycarbonyl-N″-ethylguanidino)benzylamine

Using the compound obtained in Example 625 as a starting material, the same procedure of Example 233 gave 180.8 mg of the titled compound (yield, 66%).

¹H-NMR(CDCl₃) δ: 1.10-1.21(3H,m), 1.47(9H,s), 3.32-3.48(2H,m), 4.62(2H, d, J=5.9 Hz), 6.62(1H,brs), 7.11(2H,brs), 7.25-7.60(6H,m), 7.78-7.88(2H,m), 10.70(1H,brs)

Example 628 Synthesis of N-benzoyl-3-(N′-ethylguanidno)benzylamine

A mixture of the compound (180.8 mg) obtained in Example 627 and trifluoroacetic acid (5 ml) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and, after addition of a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give 46.1 mg of the titled compound (yield, 34%).

¹H-NMR(DMSO-d₆) δ: 1.06(3H, t, 7.3 Hz), 3.11(2H, q, J=7.3 Hz), 4.40(2H, d, J=6.5 Hz), 5.30(2H,brs), 6.73(2H, d, J=8.3 Hz), 7.14(2H, d, J=8.3 Hz), 7.43-7.58(3H,m), 7.86-7.96(2H,m), 8.96(1H, t, J=6.5 Hz)

Example 629 Synthesis of 3-amino-N-benzoylbenzylamine

Using N-benzoyl-3-nitrobenzylamine as a starting material, the same procedure of Example 566 gave 985 mg of the titled compound (yield, 86%).

¹H-NMR(CDCl₃) δ: 3.69(2H,s), 4.55(2H, d, J=5.3 Hz), 6.39(1H,brs), 6.57-6.60(1H,m), 6.67(1H,s), 6.72(1H, d, J=7.7 Hz), 7.13(1H, t, J=7.9 Hz), 7.37-7.54(3H,m), 7.77(1H,s), 7.78(1H, d, J=8.3 Hz)

Example 630 Synthesis of N-benzoyl-3-thioureidobenzylamine

Using the compound obtained in Example 629 as a starting material, the same procedure of Example 3 gave 147 mg of the titled compound (yield, 58%).

¹H-NMR(DMSO-d₆) δ: 4.48(2H, d, J=5.9 Hz), 7.08(1H, d, J=7.6 Hz), 7.22-7.57(8H,m), 7.90(2H, d, J=6.6 Hz), 8.98(1H,brs), 9.68(1H,s)

Example 631 Synthesis of N-benzoyl-3-(S-ethylisothioureido)benzylamine

Using the compound obtained in Example 630 as a starting material, the same procedure of Example 626 gave 39.0 mg of the titled compound (yield, 93%).

¹H-NMR(CDCl₃) δ: 1.35(3H, t, J=7.3 Hz), 3.00(2H, q, J=7.3 Hz), 4.52(1H,brs), 4.59(2H, d, J=5.6 Hz), 6.50(1H,brs), 6.85(1H, d, J=8.1 Hz), 6.90(1H,s), 7.01(1H, d, J=7.6 Hz), 7.27(1H, dd, J=8.1, 7.6 Hz), 7.38-7.50(3H,m), 7.76-7.79(2H,m)

Example 632 Synthesis of N-benzoyl-3-(N′-t-butoxycarbonyl-N″-ethylguanidino)benzylamine

Using the compound obtained in Example 629 as a starting material, the same procedure of Example 233 gave 57 mg of the titled compound (yield, 59%).

¹H-NMR(CDCl₃) δ: 1.03-1.20(3H,m), 1.47(9H,s), 3.30-3.42(2H,m), 4.61(2H, d, J=5.6 Hz), 4.88(1H,brs), 6.91(1H,brs), 6.92-7.20 (4H,m), 7.26-7.55(5H,m), 7.82(2H, d, J=6.9 Hz)

Example 633 Synthesis of N-benzoyl-3-(N′-ethylguanidino)benzylamine monohydrochloride

Using the compound obtained in Example 632 as a starting material, the same procedure of Example 5 gave 31.7 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.14(3H, t, J=6.9 Hz), 3.21-3.38(2H,m), 4.50(2H, d, J=5.6 Hz), 7.10(1H, d, J=6.9 Hz), 7.19(1H,s), 7.24(1H, d, J=7.9 Hz), 7.34-7.71(5H,m), 7.75-7.79(3H,m), 9.04 (1H,brs), 9.46-9.59(1H,m)

Example 634 Synthesis of 1-(2-methoxy-5-nitrophenyl)ethanol

To a solution of 2-methoxy-5-nitrobenzaldehyde (450 mg) in toluene (30 ml), a solution of trimethylaluminum in hexane (3.0 ml) was added dropwise under ice cooling. After stirring at room temperature for 1 h, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 385 mg of the titled compound (yield, 79%).

¹H-NMR(CDCl₃) δ: 1.51(3H, d, J=6.3 Hz), 2.25(1H, d, J=3.3 Hz), 3.96(3H,s), 5.12-5.23(1H,m), 6.93(1H, d, J=9.2 Hz), 8.18(1H, dd, J=9.2, 2.6 Hz), 8.35(1H, d, J=2.6 Hz)

Example 635 Synthesis of N-((1-(2-methoxy-5-nitrophenyl))ethyl)phthalimide

Using the compound obtained in Example 634 as a starting material, the same procedure of Example 179 gave 358 mg of the titled compound (yield, 57%).

¹H-NMR(CDCl₃) δ: 1.87(3H, d, J=7.3 Hz), 3.87(3H,s), 5.82(1H, q, J=7.3 Hz), 6.89(1H, d, J=9.2 Hz), 7.70(2H, dd, J=5.3, 3.0 Hz), 7.81(2H, dd, J=5.3, 3.0 Hz), 8.21(1H, dd, J=9.2, 2.7 Hz), 8.54(1H, d, J=2.7 Hz)

Example 636 Synthesis of N-(1-(5-amino-2-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 635 as a starting material, the same procedure of Example 309 gave N-((1-(2-methoxy-5-nitrophenyl))ethyl)carbamic acid t-butyl ester. The resulting nitro compound was subjected to the same reaction as in Example 2 to give 165 mg of the titled compound (yield, 58%).

¹H-NMR(CDCl₃) δ: 1.39(3H, d, J=7.3 Hz), 1.42(9H,s), 3.40(2H,brs), 3.79(3H,s), 4.78-4.90(1H,m), 5.28-5.41(1H,m), 6.52-6.60(2H,m), 6.71(1H, d, J=8.4 Hz)

Example 637 Synthesis of N-(1-(2-methoxy-5-thioureidophenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 636 as a starting material, the same procedure of Example 120 gave 110 mg of the titled compound (yield, 90%).

¹H-NMR(CDCl₃) δ: 1.38(3H, d, J=6.9 Hz), 1.41(9H,s), 3.87(3H,s), 4.90-5.01(1H,m), 5.02-5.09(1H,m), 5.91(2H,brs), 6.88(1H, d, J=8.3 Hz), 7.05-7.17(2H,m), 7.58(1H,s)

Example 638 Synthesis of N-(1-(5-(S-ethylisothioureido)-2-methoxyphenyl)ethyl)carbamic acid t-butyl ester hydroiodide

Using the compound obtained in Example 637 as a starting material, the same procedure of Example 95 gave 129 mg of the titled compound (yield, 81%).

¹H-NMR(CDCl₃) δ: 1.36(3H, t, J=7.3 Hz), 1.39(3H, d, J=6.9 Hz), 1.42(9H,s), 3.02(2H, q, J=7.3 Hz), 3.83(3H,s), 4.82-4.95(1H,m), 5.10-5.28(1H,m), 6.73-7.01(3H,m)

Example 639 Synthesis of N-(1-(5-(S-ethylisothioureido)-2-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 638 as a starting material, the same procedure of Example 5 gave 112.6 mg of the titled compound quantitatively.

¹H-NMR(DMSO-d₆) δ: 1.33(3H, t, J=7.3 Hz), 1.52(3H, d, J=6.6 Hz), 3.22-3.40(2H,m), 3.89(3H,s), 4.50-4.71(1H,m), 7.18(1H, d, J=8.6 Hz), 7.31(1H, d, J=8.6 Hz), 7.49(1H,s), 8.55(2H,brs), 9.18(1H,brs), 9.74(1H,brs), 11.56(1H,brs)

Example 640 Synthesis of N-(1-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-methoxyphenyl)ethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 636 as a starting material, the same procedure of Example 233 gave 66 mg of the titled compound (yield, 62%).

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=6.9 Hz), 1.38(3H, d, J=7.0 Hz), 1.42(9H,s), 1.53(9H,s), 3.31-3.46(2H,m), 3.86(3H,s), 4.53(1H,brs), 4.90-5.03(1H,m), 5.07(1H,brs), 6.86(1H, d, J=8.9 Hz), 7.02-7.12(2H,m), 10.50(1H,brs)

Example 641 Synthesis of N-(1-(5-(N′-ethylguanidino)-2-methoxyphenyl)ethyl)amine dihydrochloride

Using the compound obtained in Example 640 as a starting material, the same procedure of Example 5 gave 58.8 mg of the titled compound quantitatively. ¹H-NMR(DMSO-d₆) δ: 1.15(3H, t, J=6.9 Hz), 1.49(3H, d, J=6.8 Hz), 3.28(2H, dq, J=6.0, 6.9 Hz), 3.88(3H,s), 4.52-4.65(1H,m), 7.14(1H, d, J=8.6 Hz), 7.18-7.26(1H,m), 7.30-7.34(1H,m), 7.43-7.58(2H,m), 7.66-7.78(1H,m), 8.36(2H,brs), 9.59(1H,brs)

Example 642 Synthesis of N-(2-(N-acetyl-N-methylamino)-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester

To a mixture of the compound (540 mg) obtained in Example 446, potassium carbonate (1.96 g) and acetonitrile (30 ml), acetyl chloride(890 mg) was added and heated under reflux for 24 h. Ethyl acetate was added to the reaction mixture, which was washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:ethyl acetate=5:1) to give 330 mg of the titled compound (yield, 55%).

¹H-NMR(CDCl₃) δ: 1.50(18H,s), 1.84(3H,s), 3.23(3H,s), 4.79(2H,s), 7.33(1H, d, J=8.4 Hz), 8.12(1H, d, J=2.3 Hz), 8.19(1H, dd, J=8.4, 2.3 Hz)

Example 643 Synthesis of N-(2-(N-acetyl-N-methylamino)-5-aminophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 642 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 1.80(3H,s), 3.15(3H,s), 3.77(2H,brs), 4.64(1H, d, J=17.2 Hz), 4.65(1H, d, J=17.2 Hz), 6.45(1H, d, J=2.3 Hz), 6.55(1H, dd, J=8.3, 2.3 Hz), 6.86(1H, d, J=8.3 Hz)

Example 644 Synthesis of N-(2-(N-acetyl-N-methylamino)-5-thioureidophenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 643 as a starting material, the same procedure of Example 120 gave the titled compound (yield, 80%).

¹H-NMR(CDCl₃) δ: 1.48(18H,s), 1.83(3H,s), 3.19(3H,s), 4.70(1H, d, J=17.2 Hz), 4.71(1H, d, J=17.2 Hz), 6.26(2H,brs), 7.14-7.26(3H,m), 8.32(1H,brs)

Example 645 Synthesis of N-(2-(N-acetyl-N-methylamino)-5-(S-ethylisothioureido)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 644 as a starting material, the same procedure of Example 95 gave the titled compound (yield, 83%).

¹H-NMR(CDCl₃) δ: 1.35(3H, t, J=6.9 Hz), 1.45(18H,s), 1.82(3H,s), 2.90-3.15(2H,m), 3.18(3H,s), 4.53(2H,brs), 4.69(1H, d, J=17.2 Hz), 4.70(1H, d, J=17.2 Hz), 6.76(1H, brs), 6.79-6.92(1H,m), 7.04(1H, d, J=7.9 Hz)

Example 646 Synthesis of N-(2-(N-acetyl-N-methylamino)-5-(S-ethylisothioureido)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 645 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 53%).

¹H-NMR(D₂O) δ: 1.43(3H, t, J=7.6 Hz), 2.37(3H,s), 3.26(2H, q, J=7.6 Hz), 3.44(3H,s), 4.12(1H, d, J=14.2 Hz), 4.14(1H, d, J=14.2 Hz), 7.50-7.60(3H,m)

Example 647 Synthesis of N-(2-(N-acetyl-N-methylamino)-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)phenylmethyl)iminodicarboxylic acid di-t-butyl ester

Using the compound obtained in Example 643 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 69%).

¹H-NMR(CDCl₃) δ: 1.19(3H, t, J=7.4 Hz), 1.47(27H,s), 1.82(3H,s), 3.20(3H,s), 3.30-3.44(2H,m), 4.70(1H, d, J=16.8 Hz), 4.71(1H, d, J=16.8 Hz), 6.85-7.05(2H,m), (7.08, 1H, d, J=7.6 Hz)

Example 648 Synthesis of N-(2-(N-acetyl-N-methylamino)-5-(N′-ethylguanidino)phenylmethyl)amine dihydrochloride

Using the compound obtained in Example 647 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 27%).

¹H-NMR(D₂O) δ: 1.24(3H, t, J=7.6 Hz), 2.36(3H,s), 3.34(2H, q, J=7.6 Hz), 3.42(3H,s), 4.09(1H, d, J=14.2 Hz), 4.12(1H, d, J=14.2 Hz), 7.43-7.53(3H,m)

Example 649 Synthesis of 2-dimethylamino-3-nitrobenzoic acid

Using 2-bromo-3-nitrobenzoic acid as a starting material, the same procedure of Example 264 gave 4.8 g of the titled compound (yield, 96%).

¹H-NMR(CDCl₃) δ: 2.99(6H,s), 7.56(1H, dd, J=7.9, 7.9 Hz), 7.91(1H, dd, J=7.9, 1.7 Hz), 8.60(1H, dd, J=7.9, 1.7 Hz)

FAB-MS(m/s) 211(M⁺+1)

Example 650 Synthesis of (2-dimethylamino-3-nitrophenyl)methanol

Using the compound obtained in Example 650 as a starting material, the same procedure of Example 132 gave 4.23 g of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 2.80(6H,s), 3.16-3.28(1H,m), 4.80(2H, d, J=4.4 Hz), 7.19(1H, dd, J=7.8, 7.8 Hz), 7.53-7.61(2H,m)

FAB-MS(m/s) 197(M⁺+1)

Example 651 Synthesis of N-(2-dimethylamino-3-nitrophenylmethyl)phthalimide

Using the compound obtained in Example 650 as a starting material, the same procedure of Example 179 gave 4.4 g of the titled compound (yield, 63%).

¹H-NMR(CDCl₃) δ: 2.84(6H,s), 4.99(2H,s), 7.09(1H, dd, J=7.9, 7.9 Hz), 7.31(1H, d, J=7.9 Hz), 7.53(1H, d, J=7.9 Hz), 7.74-7.79(2H,m) 7.87-7.91(2H,m)

FAB-MS(m/s) 325(M⁺)

Example 652 Synthesis of N-(2-dimethylamino-3-nitrophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 651 as a starting material, the same procedure of Example 309 gave 3.74 g of the titled compound (yield, 94%).

¹H-NMR(CDCl₃) δ: 1.46(9H,s), 2.77(6H,s), 4.42(2H, d, J=5.6 Hz), 5.02(1H,brs), 7.15(1H, dd, J=7.9, 7.9 Hz), 7.52(2H, d, J=7.9 Hz)

FAB-MS(m/s) 295(M⁺)

Example 653 Synthesis of N-(3-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-dimethylaminophenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 652 as a starting material, the same procedure of Example 233 gave the titled compound (yield, 71%).

¹H-NMR(CDCl₃) δ: 1.06-1.25(3H,m), 1.46(9H,s), 1.51(9H,s), 2.78(6H,s), 3.32-3.48(2H,m), 4.28-4.43(2H,m), 4.67-5.33(2H,m), 6.55-6.68(1H,m), 6.94(1H, dd, J=7.6, 7.6 Hz), 7.05-7.23(2H,m)

FAB-MS(m/s) 436(M⁺+1)

Example 654 Synthesis of N-(3-(N′-ethylguanidino)-2-dimethylaminophenylmethyl)amine trihydrochloride

Using the compound obtained in Example 653 as a starting material, the same procedure of Example 5 gave the titled compound quantitatively.

¹H-NMR(D₂O) δ: 1.22(3H, t, J=7.3 Hz), 2.90(3H,s), 2.91(3H,s), 3.33(2H, q, J=7.3 Hz), 4.32(2H,s), 7.37-7.58(3H,m)

Example 655 Synthesis of N-(5-(N′-t-butoxycarbonyl-N″-ethylguanidino)-2-hydroxyphenylmethyl)carbamic acid t-butyl ester

Using the compound obtained in Example 338 as a starting material, the same procedure of Example 2 gave the titled compound (yield, 74%).

¹H-NMR(CDCl₃) δ: 1.06(3H, t, J=7.3 Hz), 1.46(9H,s), 1.52(9H,s), 3.32-3.40(2H,m), 4.19(2H, d, J=6.9 Hz), 5.22-5.30(1H,m), 6.88-7.08(3H,m)

Example 656 Synthesis of N-(5-(N′-ethylguanidino)-2-hydroxyphenylmethyl)amine dihydrochloride

Using the compound obtained in Example 655 as a starting material, the same procedure of Example 5 gave the titled compound (yield, 77%).

¹H-NMR(D₂O) δ: 1.21(3H, t, J=7.3 Hz), 3.29(2H, q, J=7.3 Hz), 4.17(2H,s), 7.02-7.04(1H,m), 7.22-7.26(2H,m)

TEST EXAMPLES Test Example 1

Compounds of the invention were evaluated for their inhibitory effect on the presently known three NOS isoforms as compared with existing NOS inhibitors.

The following NOS inhibitors were used as control compounds:

L-NNA,

L-CPA,

L-MIN,

L-EIN,

L-NAME,

N^(G)-amino-L-arginine (L-AA),

L-NIO,

N^(G)-monomethyl-L-arginine (L-NMMA)

Crude enzyme samples of the NOS isoforms were prepared by the following procedures (Nagafuji et al., Neuroreport 6, 1541-1545, 1995).

The crude enzyme sample of N-cNOS was prepared by the following procedure. Normal untreated male Sprague Dawley (SD) rats (body weight, 300-400 g) were decapitated; the whole brain was immediately taken out from each animal and the cerebral cortex was separated on ice. Then, 5 volumes of 50 mM Tris-HCl containing 1 mM DTT (pH 7.4) was added and the mixture was homogenized for 3 min and centrifuged at 1,000×g for 10 min. The resulting supernatant was further centrifuged at 100,000×g for 60 min and a soluble cytosolic fraction of the finally obtained supernatant was used as the crude enzyme sample of N-cNOS.

The crude enzyme sample of E-cNOS was prepared by the following procedure. A cow pulmonary arterial endothielium cell (CPAE) was cultured in a MEM medium containing 20% FBS. Several days later, the cells were detached from the flask using a 0.25% tripsin solution containing 1 mM EDTA and, after addition of a suitable amount of FBS, centrifuged at 1,000 rpm for 10 min. A suitable amount of Ca- and Mg-free phosphate buffer (pH 7.4) was added to the precipitating cells and they were centrifuged at 1,000 rpm for 10 min. The same step was repeated to wash the cells which, upon addition of 50 mM Tris-HCl (pH 7.4) containing 1% Triton X-100 and 1 mM DTT, were left to stand in ice for 1 h. Subsequently, the mixture was homogenized for 3 min and kept in ice for 30 min with occasional stirring. Finally, the mixture was centrifuged at 100,000×g for 60 min and the resulting supernatant was used as the crude enzyme sample of E-cNOS.

The crude enzyme sample of iNOS was prepared by the following procedure. Rats were administered intraperitoneally with LPS (10 mg/kg) and, 6 h later, perfused in a transcardiac manner with physiological saline containing 10 U/ml of heparin; thereafter, lungs were taken out. Subsequently, 5 volumes of 50 mM Tris-HCl containing 1 mM DTT (pH 7.4) was added and the mixture was homogenized for 3 min, followed by centrifugation of the homogenate at 1,000×g for 10 min. The resulting supernatant was centrifuged at 100,000×g for 60 min and a soluble cytosolic fraction of the finally obtained supernatant was used as the crude enzyme sample of iNOS.

The method of measuring NOS activity was basically the same as already reported by the present inventors and consisted of determining quantitatively the conversion of a substrate L-[³H]arginine to a reaction product L-[³H]citrulline (Nagafuji et al., in Brain Edema IX (Ito et al., eds.) 60, pp. 285-288, 1994; Nagafuji et al., Neuroreport 6, 1541-1545, 1995).

The reaction solution consisted of 100 nM L-[³H]arginine, a prepared curde NOS enzyme sample (10-30 μg/ml protein), 1.25 mM CaCl₂, 1 mM EDTA, 10 μg/ml calmodulin, 1 mM NADPH, 100 μm tetrahydrobiopterine, 10 μm FAD, 10 μm FMN and 50 mM Tris-HCl (pH 7.4), to which one of the compounds of the invention or one of the control compounds was added.

The reaction was started by addition of L-[³H]arginine and following incubation at 37° C. for 10 min, the reaction was terminated by addition of 2 ml of 50 mM Tris-HCl (pH 5.5) containing 1 mM EDTA and placing the mixture on ice. The reaction solution was passed through a cation-exchange resin column (Dowex AG50WX-8, Na⁺ form, 3.2 ml) to separate the reaction product L-[³H]citrulline from the unreacted residual substrate L-[³H]arginine. The eluate was combined with another eluate resulting from the passage of a given amount of distilled water through the column and put into a minivial for recovery of L-[³H]citrulline. Thereafter, a scintillation fluid was added and the contained radioactivity was measured with a liquid scintillation counter to determine the amount of L-[³H]citrulline.

The activity of N-cNOS or E-cNOS was determined by subtracting the activity as detected in the absence of CaCl₂ and calmodulin from the activity as detected in the presence of CaCl₂ and calmodulin. The activity of iNOS was detected in the absence of CaCl₂ and calmodulin. The protein concentration of each crude enzyme sample was determined with a micro-assay kit of Biorad Co. Each experiment was conducted in a duplicate.

Tables 49, 50 and 51 list the mean values of IC₅₀ (the concentration necessary to inhibit 50% activity) of all test compounds against each NOS isoform, as obtained in one to four independent experiments. The tables also list the ratios of IC₅₀ values to each other as an index of selectivity.

TABLE 49 Inhibitory Potency and Selectivity of Test Compounds against Three NOS Isoforms Example No. IC₅₀ value, nM Ratio of IC₅₀ values or Control N-cNOS E-cNOS iNOS E-cNOS/ iNOS/ E-cNOS/ Compound (Type 1) (Type 3) (Type 2) N-cNOS N-cNOS iNOS 96 2.1 198.3 28.6 94.4 13.6 6.9 122 3.8 3,525.3 24,649.9 927.7 6486.8 0.1 175 4.0 199.8 n.d. 50.0 n.d. n.d. 270 4.3 3,586.1 4528.7 834.0 1053.2 0.8 131 4.5 481.1 78.2 106.9 17.4 6.2 324 4.8 2,305.6 8728.2 480.3 1818.4 0.3 171 5.0 29.2 n.d. 5.8 n.d. n.d. 104 5.2 117.8 86.5 22.7 16.6 1.4 28 5.5 n.d. 32.7 n.d. 5.9 n.d. L-MIN 5.7 152.0 247.6 26.7 43.4 0.6 14 5.9 n.d. 3,681.3 n.d. 623.9 n.d. 21 5.9 n.d. 2,606.2 n.d. 441.7 n.d. 411 5.9 341.3 n.d. 57.8 n.d. n.d. 452 6.4 3631.7 6,963.2 567.5 1088.0 0.5 137 7.1 484.6 n.d. 68.3 n.d. n.d. 7 7.6 42.4 2,123.2 5.6 279.4 0.02 162 7.9 575.7 n.d. 72.9 n.d. n.d. 173 8.2 24.1 n.d. 2.9 n.d. n.d. L-EIN 8.4 732.2 6,760.8 87.2 804.9 0.1 458 8.4 4101.1 n.d. 488.2 n.d. n.d. 47 8.8 72.9 n.d. 8.3 n.d. n.d. 112 10.8 407.6 n.d. 37.7 n.d. n.d. 177 11.6 510 n.d. 44.0 n.d. n.d. 317 12.2 238.6 n.d. 19.6 n.d. n.d. 167 13.3 365.8 n.d. 27.5 n.d. n.d. 169 14.0 41.5 n.d. 3.0 n.d. n.d. 12 14.2 538.5 239.3 37.9 16.9 2.3 L-NNA 16.9 68.2 3,464.3 4.0 205.0 0.02 288 19.9 1263.8 n.d. 63.5 n.d. n.d. 26 20.9 430.5 1,345.9 20.6 64.4 0.3 376 21.3 338.6 n.d. 15.9 n.d. n.d. 153 22.2 422.8 n.d. 19.0 n.d. n.d. 528 22.8 436.2 n.d. 19.1 n.d. n.d. 5 23.4 429.2 448.7 18.3 19.2 1.0 372 23.6 359.9 n.d. 15.3 n.d. n.d. 538 24.4 2543.3 305.9 104.2 12.5 8.3 Note: Symbol “n.d.” means not determined.

 

TABLE 50 Inhibitory Potency and Selectivity of Test Compounds against Three NOS Isoforms Example No. IC₅₀ value, nM Ratio of IC₅₀ values or Control N-cNOS E-cNOS iNOS E-cNOS/ iNOS/ E-cNOS/ Compound (Type 1) (Type 3) (Type 2) N-cNOS N-cNOS iNOS L-CPA 27.3 986.6 7,153.9 36.1 262.0 0.1 52 35.2 483.5 2,760.6 13.7 78.4 0.2 298 36.4 4141.6 n.d. 113.8 n.d. n.d. 160 36.6 477.2 n.d. 13.0 n.d. n.d. 144 37.5 898.2 n.d. 24.0 n.d. n.d. 151 37.6 262.3 n.d. 7.0 n.d. n.d. 482 39.7 1992.1 n.d. 50.2 n.d. n.d. 438 41.3 6946 n.d. 168.2 n.d. n.d. 142 44.0 662.6 n.d. 15.1 n.d. n.d. 337 44.8 5201.8 1,5473.6 116.1 345.4 0.3 355 46.0 662.5 n.d. 14.4 n.d. n.d. 533 46.1 3771.3 n.d. 81.8 n.d. n.d. 305 53.9 1706.9 n.d. 31.7 n.d. n.d. 236 56.8 325.2 n.d. 5.7 n.d. n.d. 226 57.9 1,436.8 n.d. 24.8 n.d. n.d. 110 58.1 n.d. n.d n.d. n.d. n.d. 238 63.9 1164.3 n.d. 18.2 n.d. n.d. 54 67.0 n.d. 5,023.4 n.d. 75.0 n.d. 300 69.8 492.0 n.d. 7.0 n.d. n.d. 258 72.7 1085.8 n.d. 14.9 n.d. n.d. 374 77.1 1288.8 n.d. 16.7 n.d. n.d. L-NAME 79.4 923.0 13,533.1 11.6 170.4 0.1 19 88.4 n.d. 2,404.4 n.d. 27.2 n.d. 234 88.8 1167.2 n.d. 13.1 n.d. n.d. 543 95.0 3120.6 n.d. 32.8 n.d. n.d. 267 99.6 50,081.6 4,788.8 502.8 48.1 10.5 350 105.7 15,842.9 58,397.6 149.9 552.5 0.3 281 107.9 1,620.2 n.d. 15.0 n.d. n.d. 39 116.4 n.d. 22,856.0 n.d. 196.4 n.d. 41 121.0 n.d. n.d. n.d. n.d. n.d. 193 127.8 1,541.9 n.d. 12.1 n.d. n.d. L-AA 152.5 167.0 1,281.0 1.1 8.4 0.1 341 160.2 874.0 n.d. 5.5 n.d. n.d. 30 162.6 n.d. n.d. n.d. n.d. n.d. 60 170.6 n.d. 6,745.3 n.d. 39.5 n.d. 367 193.4 3,707.3 n.d. 19.2 n.d. n.d. 285 198.9 7,305.4 n.d. 36.7 n.d. n.d. Note: Symbol “n.d.” means not determined.

 

TABLE 51 Inhibitory Potency and Selectivity of Test Compounds against Three NOS Isoforms Example No. IC₅₀ value, nM Ratio of IC₅₀ values or Control N-cNOS E-cNOS iNOS E-cNOS/ iNOS/ E-cNOS/ Compound (Type 1) (Type 3) (Type 2) N-cNOS N-cNOS iNOS L-NIO 277.0 1,226.3   457.8 4.4  1.7 2.7 339 280.5 n.d. n.d. n.d. n.d. n.d. 34 280.8 n.d. 6,760.8 n.d. 24.1 n.d. 185 298.6 3,165.1 n.d. 10.6  n.d. n.d. L-NMMA 337.8   489.9 3,480.9 1.5 10.3 0.1 Note: Symbol “n.d.” means not determined.

 

From Tables 49, 50 and 51, the following are clear:

1. The compounds of Examples 28, 96, 104, 122, 131, 171, 175, 270 and 324 are more potent in inhibiting N-cNOS than L-MIN which exhibited the strongest N-cNOS inhibitory activity in the existing NOS inhibitors;

2. From a viewpoint of the selectivity for N-cNOS compared to E-cNOS, the compounds of Examples 96, 122, 131, 175, 267, 270, 298, 324, 337, 350, 438, 452, 458, 466, 473, 538 and 560 have more selective inhibitory effect on N-cNOS than L-EIN which exhibited the highest selective inhibitory effect on N-cNOS in the existing NOS inhibitors;

3. The compounds of Examples 12, 28, 96, 104 and 131 are more potent in inhibiting iNOS than L-MIN which exhibited the strongest iNOS inhibitory activity in the existing NOS inhibitors;

4. From a viewpoint of the selectivity for iNOS compared to E-cNOS, the compounds of Examples 96, 131, 267 and 538 have more selective inhibitory effect on iNOS than L-NIO which exhibited the highest selective inhibitory effect on iNOS in the exisiting NOS inhibitors.

Test Example 2

An experiment was conducted to evaluate the effectiveness of a compound within the scope of the invention using a rat model of focal cerebral ischemia. Such models were prepared by occluding the left middle cerebral artery (MCA) in accordance with the method already reported by the present inventors (Nagafuji et al., Neurosci. Lett. 147, 159-162, 1992; Nagafuji et al., in Brain Edema IX (Ito et al., eds.) 60, pp. 285-288, 1994, Springer-Verlag; Nagafuji et al., Neuroreport 6, 1541-1545, 1995).

Eight- to nine-week old male SD rats were allowed to inhale 2% halothane (70% N₂O and 30% O₂) for inducing anesthesia, then 1% halothane to maintain, and fitted with a polyethylene catheter into the right femoral vein for drug administration. Each of the thus anesthesized rats was placed in lateral position on an operating bench. A skin incision was made between the left external auditory pore and the lateral angle of eye and incision was effected along the anterior margin of the temporal muscle down to the zygomatic arch, with the temporal muscle being later extracted with a bipolar coagulator. Under a surgical microscope, the third branch of the trigeminal nerve was identified in the bottom part of the temporal bone as running inside the temporal muscle and a small hole with a diameter of about 3 mm was opened by means of a dental drill, the blade of which had been immersed in ice-cold physiological saline, in a position between the foramen oval from which the identified third branch extended and the orbital fissure. A thin layer of the bone was removed by means of a micro-hook and a micro-needle holder.

Subsequently, the dura mater and arachnoidea were slightly cut by means of a needle (27G) and a micro-hook and the MCA trunk was occluded with a mini-clip at a proximal portion to the lenticulostriate artery (LSA)

In permanent occlusion models, both the MCA trunk and the LSA were cut off by cauterizing with a bipolar coagulator. In temporary occlusion models, only occlusion with a mini-clip was performed and the clip was removed under a surgical microscope to allow for reperfusion.

Immediately after occlusion of the MCA, either a control solvent (0.9% physiological saline, 10 μl/h) or the compound of Example 96 (0.12-3.6 μg/kg) was injected through the right femoral vein. Thereafter, an osmotic pump (Alzet) connected to the catheter was buried under the skin of each rat and sustained infusion of the solvent or the test compound was started (0.01-0.3 μg/kg/min). Finally, a gel foam that had been immersed in antibiotic-containing physiological saline was packed into the incised cavity, the wound was sutured and all animals were returned to individual cages.

The water content in the brain which was an index of brain edema formation was measured by the dry-wet method (Nagafuji et al., Neurosci. Lett. 147, 159-162, 1992) in the following manner. Forty-eight hours after the MCA occlusion, the rats were decapitated and both the right and left cerebral hemispheres were extracted from each animal within 60 seconds; the wet weight of the brain tissue of each hemisphere was measured with a chemical balance within 90 seconds. Thereafter, the hemispheres were dried in an oven at 105° C. for 3 days and their dry weights were measured. The water content in the brain was determined by the following forumula: (wet weight−dry weight)/(wet weight)×100 (%). The percentage of the water content in the stroke side (left hemisphere) to the water content in contralateral side (right hemisphere) is shown in FIG. 1.

In the experiment for evaluating the action in reducing brain infarct volume, the rats were decapitated after 3-h MCA occlusion followed by 24-h reperfusion and the whole brain was extracted; thereafter, six serial coronal sections were sliced at 2-mm intervals from the frontal lobe (Nagafuji et al., Neuroreport 6, 1541-1545, 1995). The slices were immersed in a solution of 2% 2,3,5-triphenyltetrazolium hydrochloride (TTC) in physiological saline at 37° C. for 30 min and a photograph was taken of both sides of each slice. The photographic images were read with a scanner and the infarct area in each slice was determined on a computer in accordance with the following equation: the infarct area in the stroke hemisphere=(the normal area in the contralateral hemisphere)−(the normal area in the stroke hemisphere) using an image analyzing software (NIH Image) to avoid overestamination of the infarct area due to edema formation.

The infarct volume was calculated as the total sum of the volumes of individual foci which were determined by the formula of (infarct area)×(1 mm) and the results are shown in FIG. 2.

All experimental data are expressed by mean ± standard error, with the number of animals in each group indicated within parentheses. For statistical analysis, a parametric Dunnett's multiple comparative test was conducted and the case having a risk factor (p value) of less than 0.05 was regarded as “statistically significant”.

As shown in FIG. 1, the percentage of the water content in the stroke hemisphere to the contralateral hemisphere of the control group increased to about 103.8% after 48 hours of the MCA occlusion, obviously indicating the edema formation. This increase in the percentage of the water content was reduced in a dose-dependent manner by the administration of the compound of Example 96; in the group which was given by a sustained infusion of the compound at 0.3 μg/kg/min following an intravenous bolus administration of 3.6 μg/kg, the percentage of the water content decreased to about 102.1%, which was statistically significant (p<0.01). The absolute water content in the contralateral hemisphere of the control group was 79.29±0.06%.

As shown in FIG. 2, the extensive infarction over the dorsal striatum and the cerebral cortex in the left hemisphere which was estimated about 104.2 mm³ was observed after 3-h MCA occlusion and 24-h reperfusion. This infarction could be ameliorated in a dose-dependent manner by the administration of the compound of Example 96; in the group which was given by a sustained infusion of 0.3 μg/kg/min following an intravenous bolus administration of 3.6 μg/kg, the infarct volume decreased by about 79.7%, which was statistically significant (p<0.01).

These experimental data suggest that the compounds of the invention including Exmaple 96 offer advantages that are effective and preferred for the purpose of treating cerebrovascular diseases.

INDUSTRIAL APPLICABILITY

The compounds of the invention exhibit a stronger N-cNOS or iNOS inhibiting activity than existing NOS inhibitors or they exhibit particularly high selectivity in inhibitory action against N-cNOS or iNOS among the three NOS isoforms; hence, the compounds are useful as therapeutics of the pathology in cerebrovascular diseases, in particular, occlusive cerebrovascular diseases, as well as traumatic brain injuries, seizure, headache and other pains, morphine tolerance and dependence, alzheimer's disease, Parkinson's disease, septic shocks, chronic rheumatoid arthritis, osteoarthritis, viral, or nonviral infections and diabetes. 

What is claimed is:
 1. A compound represented by the formula (1) or a possible stereoisomer or an optically active form of the compound or a pharmaceutically acceptable salt thereof:

  (where R₁ is SR₆ or NR₇R₈; R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms; R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 3-6 carbon atoms, a straight-chained or branched alkoxy group having 1-6 carbon atoms, or a nitro group; R₈ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted acyl group having 1-8 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycabonylamino group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amino group, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or 1, with the proviso that 2-benzyloxycarbonylamino-3-(4-(N′-nitro)guanidinophenyl)propionic acid, 2-t-butoxycarbonylamino-3-(4-(N′-nitro)guanidinophenyl)propionic acid, 2-amino-3-(4-(N′-nitro)guanidinophenyl)propionic acid, 2-amino-3-(4-guanidinophenyl)propionic acid, and an optically active form thereof are excluded and with the further proviso that when R₁ is NR₇R₈, then R₂ is neither a carboxyl group nor an ester thereof, and with the further proviso that R₇, R₈, R₂, R₃, R₄, R₅, Y₁, Y₂, Y₃ and Y₄ are not all hydrogen when m and n are O.
 2. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is SR₆, where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted acyl group having 1-8 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 3. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is SR₆, where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or R₂ and R₃ may combine together to form a 3- to 8-membered ring; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 4. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 5. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ and R₃ are each a hydrogen atom; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 6. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which; the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 7. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which; the substituents other than Y₁, Y₂, Y₃ and Y₄ are p-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 8. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which R₁ is NR₇R₈, where R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, or a nitro group and R₈ is a hydrogen atom, a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 9. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is NR₇R₈, where R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, or a nitro group and R₈ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitorogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 10. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is a nitroamino or ethylamino group; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or R₂ and R₃ may combine together to form a 3- to 8-membered ring; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 11. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a nitroamino or ethylamino group; R₂ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 12. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which; the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a nitroamino or ethylamino group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 13. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which; the substituents other than Y₁, Y₂, Y₃ and Y₄ are p-substituted on the benzene nucleus; R₁ is a nitroamino or ethylamino group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 14. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a nitroamino or ethylamino group; R₂ and R₃ are each a hydrogen atom; R₄ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 15. A therapeutic composition for treatment of a cerebrovascular disease, Alzheimer's disease, pain, morphine tolerance or dependence, Parkinson's disease, or traumatic brain injuries, containing an N-cNOS inhibitor as an effective ingredient in an N-cNOS effective amount for the therapy of said disease, and a pharmaceutically acceptable adjuvant, wherein said N-cNOS inhibitor is a compound represented by the formula (1) of claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof.
 16. A therapeutic composition for treatment of septic shock, chronic rheumatoid arthritis, osteoarthritis, viral or nonviral infection, or diabetes, containing as an effective ingredient an iNOS inhibitor in an iNOS effective amount for said treatment, and a pharmaceutically acceptable diluent, wherein said iNOS inhibitor is a compound represented by the formula (1) of claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof.
 17. The therapeutic composition for cerebrovascular disease according to claim 15 wherein said N-cNOS inhibitor is N-(5-(S-ethylisothioureido)-2-methhoxyphenylmethyl)amine or a pharmaceutically acceptable salt thereof.
 18. A compound according to claim 1 which is selected form the group consisting of: N-(1-(3-(S-methylisothioureido)phenyl)-1-methyl)ethyl)amine; N-(1-methyl-1-(3-(N′-nitroguanidino)phenyl)ethyl)amine; N-(1-(3-(S-methylisothioureido)phenyl)ethyl)amine; N-(1(3-(N′-nitoroguanidino)phenyl)ethyl)amine; N-(1-(3-(N′-nitoroguanidino)phenyl)propyl)amine; N-(3-(S-methylisothioureido)phenylmethyl)amine; N-(3-(S-ethylisothioureido)phenylmethyl)amine; N-(3-(S-ethylisothioureido)phenylmethyl)methylamine; N-(4-(S-methylisothioureido)phenylethyl)amine; N-(1-(3-(S-ethylisothioureido)phenyl)-1-methyl)ethyl)amine; N-(4-(S-ethylisothioureido)phenylethyl)dimethylamine; N-(4-(S-ethylisothioureido)phenylethyl)amine; N-(3-(S-methylisothioureido)phenylethyl)methylamine; N-(1-(3-(S-ethylisothioureido)phenyl)ethyl)methylamine; N-(1-(3-(S-ethylisothioureido)phenyl)cyclopentyl)amine; N-(1-(3-(N′-nitoroguanidino)phenyl)cyclopentyl)amine; N-(1-(3-(S-methylisothioureido)phenyl)cyclohexyl)amine; N-(1-(3-(S-ethylisothioureido)phenyl)cyclohexyl)amine; N-(1-(3-(N′-nitoroguanidino)phenyl)cyclohexyl)amine; N-(1-(3-(S-ethylisothioureido)phenyl)ethyl)amine; N-(1-(3-(N′-nitoroguanidino)phenyl)cyclobutyl)amine; N-(1-(3-(S-methylisothioureido)phenyl)cyclobutyl)amine; N-(1-(3-(S-ethylisothioureido)phenyl)cyclobutyl)amine; N-(1-(3-(S-ethylisothioureido)phenyl)cyclopropyl)amine; N-(5-(S-ethylisothioureido)-2-methoxyphenylmethyl)amine; N-(3-(S-ethylisothioureido)-2-methylyphenylmethyl)amine; N-(2-chloro-3-(S-ethylisothioureido)phenylmethyl)amine; N-(1-(3-(S-ethylisothioureido)phenyl)propyl)amine; N-(2-dimethylamino-5-(N′-ethylguanidino)phenylmethyl)amine; N-(2-dimethylamino-5-(S-ethylisothioureido)phenylmethyl)amine; N-(5-(S-ethylisothioureido)-2-(N-ethyl-N-methylamino)phenylmethyl)amine; N-(2,6-dimethoxy-3-(S-etylisothioureido)phenylmethyl)mine; N-(2-ethoxy-5-(S-ethylisothioureido)phenylmethyl)amine; N-(2-benzyloxy-5-(S-ethylisothioureido)phenylmethyl)amine; N-(1-(5-(S-ethylisothioureido)-2-methoxyphenyl)-1-methylethyl)amine; N-(3-(N′-ethylguanidino)phenylmethyl)amine; N-(3-(S-ethylisothioureido)-2-methylphenylmethyl)methylamine: N-(2-benzylamino-5-(S-ethylisothioureido)phenylmethyl)amine; N-(5-(N′-ethylguanidino)-2-fluorophenylmethyl)amine; N-(5-(S-ethylisothioureido)-2-methylaminophenylmethyl)amine; N-(2-ethylamino-(S-ethylisothioureido)phenylmethyl)amine; N-(2-ethyl-5-(N′-ethylguanidino)phenylmethyl)amine; N-(5-(N′-ethylguanidino)-2-methylphenylmethyl)amine; N-(2-(4-(S-ethylisothioureido)-2-methoxyphenyl)ethyl)amine; N-(3-(N′-ethylguanidino)-2-methylphenylmethyl)amine; N-(2-chloro-3-(N′-ethylguanidino)phenylmethyl)amine; and N-(2-chloro-5-(N′-ethylguanidino)phenylmethyl)amine; or a possible optically active form of the compound or a pharmaceutically acceptable salt thereof.
 19. A compound represented by the formula (1), a possible stereoisomer thereof or an optically active form of the compound or a pharmaceutically acceptable salt thereof:

  (where R₁ is SR₆ or NHR₇; where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms; R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, or a nitro group; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is 0, with the proviso that 2-benzyloxycarbonylamino-3-(4-(N′-nitro)guanidinophenyl)-propionic acid, 2-t-butoxycarbonylamino-3-(4-(N′-nitro)guanidinophenyl)-propionic acid, 2-amino-3-(4-(N′-nitro)guanidinophenyl)propionic acid, 2-amino-3-(4-guanidinophenyl)propionic acid, and an optically active form thereof are excluded, and with the further proviso that when R₁ is NR₇R₈, then R₂ is neither a carboxyl group nor an ester thereof, and with the further proviso that when m and n are both O, R₇, R₈, R₂, R₃, R₄, R₅, Y₁, Y₂, Y₃ and Y₄ are not all hydrogen.
 20. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is SR₆, where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 21. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is SR₆, where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 22. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atom, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₂ to form a 3- to 8-membered ring; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 23. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted; R₁ is a methylthio or ethylthio group; R₂ and R₃ are each a hydrogen atom; R₄ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 24. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; and n and m are each
 0. 25. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are p-substituted on the benzene nucleus; R₁ is a methylthio or ethylthio group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is 1; and m is
 0. 26. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is NHR₇, where R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms, or a nitro group; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 27. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is NHR₇, where R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms or a nitro group; R₂ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or a carboxyl group, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₂ to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 28. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is a nitroamino group; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 29. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a nitroamino group; R₂ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₃ to form a 3- to 8-membered ring; R₃ is a straight-chained or branched alkyl group having 1-6 carbon atoms or may combine with R₂ to form a 3- to 8-membered ring; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; and n is an integer of 0 or 1; and m is
 0. 30. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a nitroamino group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; and n and m are each
 0. 31. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are p-substituted on the benzene nucleus; R₁ is a nitroamino group; R₂ is a hydrogen atom or a methyl or ethyl group; R₃ is a hydrogen atom or a methyl group; R₄ and R₅ are each a hydrogen atom; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is 1; and m is
 0. 32. A compound of the general formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: the substituents other than Y₁, Y₂, Y₃ and Y₄ are m-substituted on the benzene nucleus; R₁ is a nitroamino group; R₂ and R₃ are each a hydrogen atom; R₄ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ are each a hydrogen atom; n is an integer of 0 or 1; and m is
 0. 33. A compound according to claim 19 which is N-(4-(S-methylisothioureido)phenylethyl)amine or a pharmaceutically acceptable salt thereof.
 34. A compound according to claim 19 which is N-(4-(S-ethylisothioureido)phenylethyl)amine or a pharmaceutically acceptable salt thereof.
 35. A therapeutic composition for treatment of cerebrovascular disease, containing an N-cNOS inhibitor as an effective ingredient in an N-cNOS inhibiting effective amount for the therapy of said disease, and a pharmaceutically acceptable adjuvant, wherein said N-cNOS inhibitor is a compound represented by the formula (1) according to claim 19 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof.
 36. The therapeutic composition for cerebrovascular disease of claim 35 wherein said N-cNOS inhibitor is N-(4-(S-methylisothioureido)phenylethyl)amine or a pharmaceutically acceptable salt thereof.
 37. The therapeutic composition for cerebrovascular disease of claim 35 wherein the N-cNOS inhibitor is N-(4-(S-ethylisothioureido)phenylethyl)amine or a pharmaceutically acceptable salt thereof.
 38. A therapeutic composition for treatment of septic shock containing as an effective ingredient an iNOS-effective amount sufficient for said treatment of an iNOS compound represented by the compound of claim 19 or a possible stereoisomer or optically active form or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
 39. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is SR₆, where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or R₂ and R₃ may combine together to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted acyl group having 1-8 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 40. A compound of the general formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is NR₇R₈, where R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms or a nitro group, and R₈ is a hydrogen atom, a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or R₂ and R₃ may combine together to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxy-carbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆, or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 41. A therapeutic composition for cerebrovascular diseases containing a pharmaceutical carrier and as an effective ingredient an amount sufficient therefor of an N-cNOS inhibitor compound of the formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is SR₆, where R₆ is an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms or a straight-chained or branched alkenyl group having 2-6 carbon atoms; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or R₂ and R₃ may combine together to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, an optionally substituted acyl group having 1-8 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆ or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 42. A therapeutic composition for cerebrovascular diseases containing a pharmaceutical carrier and as an effective ingredient an amount sufficient therefor of an N-cNOS inhibitor compound of the formula (1) according to claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof, in which: R₁ is NR₇R₈, where R₇ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, a cyclic alkyl group having 3-8 carbon atoms or a nitro group, and R₈ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms; R₂ and R₃ which may be the same or different are each a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or R₂ and R₃ may combine together to form a 3- to 8-membered ring; R₄ is a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or an amidino group that may be substituted on the nitrogen atom with a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-8 carbon atoms or a nitro group, or may combine with R₅ to form a 3- to 8-membered ring; R₅ is a hydrogen atom or a straight-chained or branched alkyl group having 1-6 carbon atoms, or may combine with R₄ to form a 3- to 8-membered ring; Y₁, Y₂, Y₃ and Y₄ which may be the same or different are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms that may be substituted by 1-3 halogen atoms, a cyclic alkyl group having 3-6 carbon atoms that may be substituted by 1-3 halogen atoms, a straight-chained or branched alkenyl group having 2-6 carbon atoms, a straight-chained or branched alkynyl group having 2-6 carbon atoms, an optionally substituted straight-chained or branched alkoxy group having 1-6 carbon atoms, a straight-chained or branched alkylthio group having 1-6 carbon atoms, NY₅Y₆, or COY₇; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, an optionally substituted straight-chained or branched alkyl group having 1-6 carbon atoms, or an optionally substituted cyclic alkyl group having 3-6 carbon atoms, an acyl group having 1-8 carbon atoms, an alkoxycarbonyl group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms, or Y₅ and Y₆ may combine together to form a 3- to 8-membered ring; Y₇ is a hydrogen atom, a hydroxyl group, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms, an alkoxy group of which the alkyl portion is a straight-chained or branched alkyl group having 1-6 carbon atoms or NY₅Y₆; where Y₅ and Y₆ which may be the same or different are each a hydrogen atom, a straight-chained or branched alkyl group having 1-6 carbon atoms or a cyclic alkyl group having 3-6 carbon atoms; and n and m are each an integer of 0 or
 1. 43. A therapeutic composition for Parkinson's disease containing as an effective ingredient an amount sufficient therefor of an iNOS inhibitor compound represented by the formula (1) of claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
 44. A therapeutic composition for traumatic brain injuries containing as an effective ingredient an amount sufficient therefor of an iNOS inhibitor compound represented by the formula (1) of claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
 45. A therapeutic composition for treatment of seizure containing as an effective ingredient an amount sufficient therefor of an iNOS inhibitor compound represented by the formula (1) of claim 1 or a possible stereoisomer or optically active form of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant. 